Indole compounds and pharmaceutical use thereof

ABSTRACT

Provided is an agent for the treatment or prophylaxis of inflammatory diseases, allergic diseases, autoimmune diseases, transplant rejection or the like. 
     A compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof: 
     
       
         
         
             
             
         
       
     
     wherein each symbol is as described in the specification.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to an indole compound and a pharmaceuticaluse thereof. More particularly, the present invention relates to acompound for the prophylaxis or treatment of inflammatory diseases,allergic diseases, autoimmune diseases, transplant rejection and thelike, by suppression of functional of Th2 cells and/or mast cells byinhibition of inducible T cell kinase (ITK), and use thereof.

BACKGROUND OF THE INVENTION

ITK is a non-receptor type tyrosine kinase belonging to 15 the Tecfamily and essential for the activation of T cells, and is mainlyexpressed in T cells, mast cells and natural killer cells. ITK isactivated in T cells upon stimulation of T cell receptor (TCR), and isactivated in mast cells upon activation of high-affinity immunoglobulin(Ig) E receptor. Subsequent to the receptor stimulation in T cells, Lck,which is one member of the Src tyrosine kinase family, phosphorylatesY511 in the ITK kinase domain activation loop. The activated ITK is,together with Zap-70, necessary for the phosphorylation and activationof PLC-γ. PLC-γ catalyzes formation of inositol 1,4,5-trisphosphoricacid and diacylglycerol, causing calcium mobilization and PKCactivation, respectively. These events activate many down streampathways, and finally cause cytokine production in T cells anddegranulation in mast cells.

Studies using ITK knockout mouse have confirmed that ITK is involved inthe differentiation of Th2 cells. Th2 cell is one kind of CD4 positivehelper T cells (Th cells), which differentiates from naive T cells byantigen stimulation, and produces cytokine. Cytokines such asinterleukin (IL)-4, IL-5, IL-13 and the like produced by Th2 cells arecalled Th2 cytokine and are known to be involved in the mechanism ofallergic disease and the like, since it promotes antibody production byplasma cells differentiated from B cells and activates cells such aseosinophils (one kind of granulocytes) and the like. Like Th2 cell, Th1cell that differentiates from naive T cells produces so-called Th1cytokines such as interferon (IFN)-γ and the like, and Th1 cell and Th2cell maintain an equilibrium relation called Th1/Th2 balance bysuppressing functions of each other. An imbalance toward either cytokineis considered to cause diseases specific to each of them. ITK knockoutmouse has been reported to selectively inhibit Th2 cell differentiationand Th2 cytokine production.

Moreover, it has been reported that ITK inhibition inhibits activationof mast cells.

Mast cell contains various chemical mediators such as histamine. When anantigen is bound to IgE bound to the cell surface, the establishedcrosslinking triggers cell activation, which consequently causes releaseof its content (chemical mediators such as histamine and the like)(degranulation). Of the chemical mediators released from the mast cells,histamine and the like have a bronchial smooth muscle constrictionaction, a blood vessel permeability enhancing effect, a mucous secretoryaction and the like and cause asthma and allergic diseases.

Therefore, an ITK inhibitor that suppresses growth of Th2 cell andproduction of Th2 cytokine, and/or suppresses degranulation andproduction of histamine and the like by suppression of activation ofmast cells is expected to show effect as an agent for the treatment orprophylaxis of the diseases involving growth of Th2 cell, production ofTh2 cytokine, degranulation, production of histamine and the like, forexample, inflammatory diseases, allergic diseases and the like.

Recently, ITK is suggested to be also involved in the activation of Th17cell, which is one kind of Th cells, and an ITK inhibitor is expected toshow effect as an agent for the treatment or prophylaxis of the diseasesinvolving Th17 cell, such as autoimmune diseases (e.g., rheumatism andthe like). In addition, ITK is suggested to be involved in amixed-lymphocyte reaction. Thus, an ITK inhibitor is expected to showeffect as an inhibitor of rejection in transplantation. Furthermore, ITKis suggested to be involved in HIV infection. Thus, an ITK inhibitor isexpected to show effect as a prophylactic or therapeutic agent for HIVinfection.

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

The present invention aims to provide an agent for the treatment orprophylaxis of inflammatory diseases, an agent for the treatment orprophylaxis of allergic diseases, an agent for the treatment orprophylaxis of autoimmune diseases, an inhibitor of rejection intransplantation and the like, which are based on an ITK inhibitoryaction.

Means of Solving the Problems

The present inventors have conducted intensive studies in an attempt todevelop an agent for the treatment or prophylaxis of inflammatorydiseases, an agent for the treatment or prophylaxis of allergicdiseases, an agent for the treatment or prophylaxis of autoimmunediseases, an inhibitor of rejection in transplantation and the like,which are based on an ITK inhibitory action, and found an indolecompound having an ITK inhibitory action, which resulted in thecompletion of the present invention.

Accordingly, the present invention provides the following.

[1] A compound represented by the following formula [I] or apharmaceutically acceptable salt thereof:

wherein,

R¹ is

(1) a hydrogen atom,(2) a hydroxy group, or(3) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀aryl group(s);R² and R³ are the same or different and each is(1) a hydrogen atom, or(2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a hydroxy group, and    -   (b) a C₁₋₆ alkoxy group; and        R⁴ is a group represented by

which is bonded to the 5-position or the 6-position of the indole ring,

-   -   wherein    -   R⁵ is    -   (1) a hydrogen atom, or    -   (2) a C₁₋₆ alkyl group, and    -   R⁶ is    -   (1) a hydrogen atom,    -   (2) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group,        -   (c) a carboxy group,        -   (d) a C₁₋₆ alkoxy-carbonyl group,        -   (e) a C₆₋₁₀ aryl group,        -   (f) a C₆₋₁₀ aryloxy group,        -   (g) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s),        -   (h) a 5- or 6-membered unsaturated heterocyclic group            optionally substituted by C₁₋₆ alkyl group(s), and        -   (i) a 5- or 6-membered saturated heterocyclic group,    -   (3) a C₁₋₆ alkoxy group,    -   (4) a C₆₋₁₀ aryl group, or    -   (5) a 5- or 6-membered unsaturated heterocyclic group optionally        substituted by 1 to 3 substituents selected from        -   (a) a hydroxy group, and        -   (b) a C₁₋₆ alkoxy group, or    -   R⁵ and R⁶ form, together with the nitrogen atom they are bonded        to, a 5- or 6-membered cyclic amine (said cyclic amine is        optionally condensed with 5- or 6-membered unsaturated        heterocycle) optionally substituted by 1 to 3 substituents        selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkyl group,        -   (c) a C₁₋₆ alkoxy group, and        -   (d) a C₁₋₆ alkoxy-carbonyl group;    -   R⁷ is    -   (1) a hydrogen atom, or    -   (2) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group, and        -   (c) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s), and R⁸ is    -   (1) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀ aryl            group(s),        -   (c) a C₃₋₆ cycloalkyl group optionally substituted by C₁₋₆            alkoxy group(s),        -   (d) a C₆₋₁₀ aryl group,        -   (e) a 5- or 6-membered unsaturated heterocyclic group            optionally substituted by oxo group(s),        -   (f) a 5- to 8-membered saturated heterocyclic group            optionally substituted by 1 to 3 substituents selected from            -   (i) a hydroxy group,            -   (ii) a C₁₋₆ alkyl group optionally substituted by 1 to 3                substituents selected from a hydroxy group and a C₁₋₆                alkoxy group,            -   (iii) a C₁₋₆ alkoxy group, and            -   (iv) an oxo group,        -   (g) a C₃₋₆ cycloalkyloxy group,        -   (h) a C₆₋₁₀ aryloxy group,        -   (i) a 5- or 6-membered unsaturated heterocyclyloxy group,        -   (j) a 5- or 6-membered saturated heterocyclyloxy group, and        -   (k) an amino group optionally mono- or di-substituted by            substituents selected from            -   (i) a C₁₋₆ alkyl group optionally substituted by 1 to 3                substituents selected from a hydroxy group, a carboxy                group and a carboxy-C₁₋₆ alkoxy group,            -   (ii) a C₁₋₆ alkyl-carbonyl group optionally substituted                by 1 to 3 substituents selected from a hydroxy group and                a C₁₋₆ alkoxy group,            -   (iii) a C₁₋₆ alkoxy-carbonyl group optionally                substituted by C₆₋₁₀ aryl group(s), and            -   (iv) a C₃₋₆ cycloalkyl-carbonyl group optionally                substituted by C₁₋₆ alkoxy group(s),    -   (2) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀ aryl        group(s),    -   (3) a C₃₋₆ cycloalkyl group optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group, and        -   (b) a C₁₋₆ alkoxy group,    -   (4) a C₁₋₁₀ aryl group optionally substituted by C₁₋₆ alkyl        group(s) optionally substituted by 1 to 3 halogen atoms,    -   (5) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) optionally substituted by C₆₋₁₀ aryl group(s),    -   (6) a 5- or 6-membered unsaturated heterocyclic group optionally        substituted by C₁₋₆ alkyl group(s),    -   (7) a 5- or 6-membered saturated heterocyclic group optionally        substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkyl group,        -   (b) a C₁₋₆ alkyl-carbonyl group, and        -   (c) an oxo group,    -   (8) a C₃₋₆ cycloalkyloxy group, or    -   (9) a C₆₋₁₀ aryl-carbonyl group, or    -   R¹ and R⁸ form, together with the nitrogen atom and carbon atom        they are bonded to, a 5- or 6-membered cyclic amine substituted        by an oxo group and optionally further substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkyl group optionally substituted by hydroxy            group(s),        -   (c) a C₁₋₆ alkoxy group, and        -   (d) a C₃₋₆ cycloalkyl group.            [2] A compound represented by the following formula [I-a] or            a pharmaceutically acceptable salt thereof:

wherein,

R¹ is

(1) a hydrogen atom,(2) a hydroxy group, or(3) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀ aryl group(s);R² and R³ are the same or different and each is(1) a hydrogen atom, or(2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a hydroxy group, and    -   (b) a C₁₋₆ alkoxy group;        R^(7′) is a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from    -   (a) a hydroxy group,    -   (b) a C₁₋₆ alkoxy group, and    -   (C) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s), and

R⁸ is

(1) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a hydroxy group,    -   (b) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀ aryl        group(s),    -   (c) a C₃₋₆ cycloalkyl group optionally substituted by C₁₋₆        alkoxy group(s),    -   (d) a C₆₋₁₀ aryl group,    -   (e) a 5- or 6-membered unsaturated heterocyclic group optionally        substituted by oxo group(s),    -   (f) a 5- to 8-membered saturated heterocyclic group optionally        substituted by 1 to 3 substituents selected from (i) a hydroxy        group,        -   (ii) a C₁₋₆ alkyl group optionally substituted by 1 to 3            substituents selected from a hydroxy group and a C₁₋₆ alkoxy            group,        -   (iii) a C₁₋₆ alkoxy group, and        -   (iv) an oxo group,    -   (g) a C₃₋₆ cycloalkyloxy group,    -   (h) a C₆₋₁₀ aryloxy group,    -   (i) a 5- or 6-membered unsaturated heterocyclyloxy group,    -   (j) a 5- or 6-membered saturated heterocyclyloxy group, and    -   (k) an amino group optionally mono- or di-substituted by        substituents selected from        -   (i) a C₁₋₆ alkyl group optionally substituted by 1 to 3            substituents selected from a hydroxy group, a carboxy group            and a carboxy-C₁₆ alkoxy group,        -   (ii) a C₁₋₆ alkyl-carbonyl group optionally substituted by 1            to 3 substituents selected from a hydroxy group and a C₁₋₆            alkoxy group,        -   (iii) a C₁₋₆ alkoxy-carbonyl group optionally substituted by            C₆₋₁₀ aryl group(s), and        -   (iv) a C₃₋₆ cycloalkyl-carbonyl group optionally substituted            by C₁₋₆ alkoxy group(s),            (2) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀ aryl            group(s),            (3) a C₃₋₆ cycloalkyl group optionally substituted by 1 to 3            substituents selected from    -   (a) a hydroxy group, and    -   (b) a C₁₋₆ alkoxy group,        (4) a C₆₋₁₀ aryl group optionally substituted by C₁₋₆ alkyl        group(s) optionally substituted by 1 to 3 halogen atoms,        (5) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) optionally substituted by C₆₋₁₀ aryl group(s),        (6) a 5- or 6-membered unsaturated heterocyclic group optionally        substituted by C₁₋₆ alkyl group(s),        (7) a 5- or 6-membered saturated heterocyclic group optionally        substituted by 1 to 3 substituents selected from    -   (a) a C₁₋₆ alkyl group,    -   (b) a C₁₋₆ alkyl-carbonyl group, and    -   (c) an oxo group,        (8) a C₃₋₆ cycloalkyloxy group, or        (9) a C₆₋₁₀ aryl-carbonyl group, or        R^(7′) and R⁸ form, together with the nitrogen atom and carbon        atom they are bonded to, a 5- or 6-membered cyclic amine        substituted by an oxo group and optionally further substituted        by 1 to 3 substituents selected from    -   (a) a hydroxy group,    -   (b) a C₁₋₆ alkyl group optionally substituted by hydroxy        group(s),    -   (c) a C₁₋₆ alkoxy group, and    -   (d) a C₃₋₆ cycloalkyl group.        [3] The compound according to the above-mentioned [2], wherein        R¹ is a hydrogen atom; and        R² and R³ are the same or different and each is a C₁₋₆ alkyl        group,        or a pharmaceutically acceptable salt thereof.        [4] The compound according to the above-mentioned [3], wherein        R^(7′) is a C₁₋₆ alkyl group; and        R⁸ is a C₁₋₆ alkyl group substituted by 1 to 3 substituents        selected from    -   (a) a hydroxy group,    -   (b) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀ aryl        group(s),    -   (c) a C₃₋₆ cycloalkyl group optionally substituted by C₁₋₆        alkoxy group(s),    -   (d) a C₆₋₁₀ aryl group,    -   (e) a 5- or 6-membered unsaturated heterocyclic group optionally        substituted by oxo group(s),    -   (f) a 5- to 8-membered saturated heterocyclic group optionally        substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group,        -   (ii) a C₁₋₆ alkyl group optionally substituted by 1 to 3            substituents selected from a hydroxy group and a C₁₋₆ alkoxy            group,        -   (iii) a C₁₋₆ alkoxy group, and        -   (iv) an oxo group,    -   (g) a C₃₋₆ cycloalkyloxy group,    -   (h) a C₆₋₁₀ aryloxy group,    -   (i) a 5- or 6-membered unsaturated heterocyclyloxy group,    -   (j) a 5- or 6-membered saturated heterocyclyloxy group, and    -   (k) an amino group optionally mono- or di-substituted by        substituents selected from        -   (i) a C₁₋₆ alkyl group optionally substituted by 1 to 3            substituents selected from a hydroxy group, a carboxy group            and a carboxy-C₁₋₆ alkoxy group,        -   (ii) a C₁₋₆ alkyl-carbonyl group optionally substituted by 1            to 3 substituents selected from a hydroxy group and a C₁₋₆            alkoxy group,        -   (iii) a C₁₋₆ alkoxy-carbonyl group optionally substituted by            C₆₋₁₀ aryl group(s), and        -   (iv) a C₃₋₆ cycloalkyl-carbonyl group optionally substituted            by C₁₋₆ alkoxy group(s), or a pharmaceutically acceptable            salt thereof.            [5] A compound selected from the following formulas

or a pharmaceutically acceptable salt thereof.[6] A pharmaceutical composition comprising the compound according toany one of the above-mentioned [1] to [5], or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier.[7] An ITK inhibitor comprising the compound according to any one of theabove-mentioned [1] to [5], or a pharmaceutically acceptable saltthereof.[8] An agent for the treatment or prophylaxis of an inflammatorydisease, comprising the compound according to any one of theabove-mentioned [1] to [5], or a pharmaceutically acceptable saltthereof.[9] The agent according to the above-mentioned [8], wherein theinflammatory disease is rheumatoid arthritis.[10] An agent for the treatment or prophylaxis of an allergic disease,comprising the compound according to any one of the above-mentioned [1]to [5], or a pharmaceutically acceptable salt thereof.[11] An agent for the treatment or prophylaxis of an autoimmune disease,comprising the compound according to any one of the above-mentioned [11]to [5], or a pharmaceutically acceptable salt thereof.[12] The agent according to the above-mentioned [11], wherein theautoimmune disease is rheumatoid arthritis.[13] An inhibitor of rejection in transplantation, comprising thecompound according to any one of the above-mentioned [1] to [5], or apharmaceutically acceptable salt thereof.[14] A method of inhibiting ITK in a mammal, comprising is administeringa pharmaceutically effective amount of the compound according to any oneof the above-mentioned [1] to [5], or a pharmaceutically acceptable saltthereof, to the mammal.[15] A method for treating or preventing an inflammatory disease in amammal, comprising administering a pharmaceutically effective amount ofthe compound according to any one of the above-mentioned [1] to [5], ora pharmaceutically acceptable salt thereof, to the mammal.[16] The method according to the above-mentioned [15], wherein theinflammatory disease is rheumatoid arthritis.[17] A method for treating or preventing an allergic disease in amammal, comprising administering a pharmaceutically effective amount ofthe compound according to any one of the above-mentioned [1] to [5], ora pharmaceutically acceptable salt thereof, to the mammal.[18] A method for treating or preventing an autoimmune disease to amammal, comprising administering a pharmaceutically effective amount ofthe compound according to any one of the above-mentioned [1] to [5], ora pharmaceutically acceptable salt thereof, to the mammal.[19] The method according to the above-mentioned [18], wherein theautoimmune diseases is rheumatoid arthritis.[20] A method of suppressing rejection in transplantation in a mammal,comprising administering a pharmaceutically effective amount of thecompound according to any one of the above-mentioned [1] to [5], or apharmaceutically acceptable salt thereof, to the mammal.[21] Use of the compound according to any one of the above-mentioned [1]to [5], or a pharmaceutically acceptable salt thereof, for producing anagent for the treatment or prophylaxis of an inflammatory disease.[22] The use according to the above-mentioned [21], wherein theinflammatory disease is rheumatoid arthritis.[23] Use of the compound according to any one of the above-mentioned [1]to [5], or a pharmaceutically acceptable salt thereof, for producing anagent for the treatment or prophylaxis of an allergic disease.[24] Use of the compound according to any one of the above-mentioned [1]to [5], or a pharmaceutically acceptable salt thereof, for producing anagent for the treatment or prophylaxis of an autoimmune disease.[25] The use according to the above-mentioned [24], wherein theautoimmune diseases is rheumatoid arthritis.[26] Use of the compound according to any one of the above-mentioned [1]to [5], or a pharmaceutically acceptable salt thereof, for producing aninhibitor of rejection in transplantation.[27] A commercial kit comprising (a) a pharmaceutical compositioncomprising the compound according to any one of the above-mentioned [1]to [5], or a pharmaceutically acceptable salt thereof as an activeingredient and (b) a written description associated therewith, whichstates that the pharmaceutical composition can or should be used fortreating or preventing an inflammatory disease, an allergic disease oran autoimmune disease.[28] A commercial package comprising (a) a pharmaceutical compositioncomprising the compound according to any one of the above-mentioned [1]to [5], or a pharmaceutically acceptable salt thereof as an activeingredient and (b) a written description associated therewith, whichstates that the pharmaceutical composition can or should be used fortreating or preventing an inflammatory disease, an allergic disease oran autoimmune disease.[1′] A compound represented by the following formula [I′] or apharmaceutically acceptable salt thereof, or a solvate thereof:

wherein,

R^(1′) is

(1) a hydrogen atom,(2) a hydroxy group, or(3) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀ aryl group(s);R^(2′) and R^(3′) are the same or different and each is(1) a hydrogen atom, or(2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a hydroxy group, and    -   (b) a C₁₋₆ alkoxy group; and        R^(4′) is a group represented by

which is bonded to the 5-position or the 6-position of the indole ring,

-   -   wherein    -   R^(5′) is    -   (1) a hydrogen atom, or    -   (2) a C₁₋₆ alkyl group, and    -   R^(6′) is    -   (1) a hydrogen atom,    -   (2) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group,        -   (c) a carboxy group,        -   (d) a C₁₋₆ alkoxy-carbonyl group,        -   (e) a C₆₋₁₀ aryl group,        -   (f) a C₆₋₁₀ aryloxy group,        -   (g) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s),        -   (h) a 5- or 6-membered unsaturated heterocyclic group            optionally substituted by C₁₋₆ alkyl group(s), and        -   (i) a 5- or 6-membered saturated heterocyclic group,    -   (3) a C₁₋₆ alkoxy group,    -   (4) a C₆₋₁₀ aryl group, or    -   (5) a 5- or 6-membered unsaturated heterocyclic group optionally        substituted by 1 to 3 substituents selected from        -   (a) a hydroxy group, and        -   (b) a C₁₋₆ alkoxy group, or    -   R^(5′) and R^(6′) form, together with the nitrogen atom they are        bonded to, a 5- or 6-membered cyclic amine (said cyclic amine is        optionally condensed with 5- or 6-membered unsaturated        heterocycle), which is optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkyl group,        -   (c) a C₁₋₆ alkoxy group, and        -   (d) a C₁₋₆ alkoxy-carbonyl group;    -   R^(7″) is    -   (1) a hydrogen atom, or    -   (2) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group, and        -   (c) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s), and    -   R⁸ is    -   (1) a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀ aryl            group(s),        -   (c) a C₃₋₆ cycloalkyl group optionally substituted by C₁₋₆            alkoxy group(s),        -   (d) a C₆₋₁₀ aryl group,        -   (e) a 5- or 6-membered unsaturated heterocyclic group            optionally substituted by oxo group(s),        -   (f) a 5- to 8-membered saturated heterocyclic group            optionally substituted by 1 to 3 substituents selected from            -   (i) a hydroxy group,            -   (ii) a C₁₋₆ alkyl group optionally substituted by 1 to 3                substituents selected from a hydroxy group and a C₁₋₆                alkoxy group,            -   (iii) a C₁₋₆ alkoxy group, and            -   (iv) an oxo group,        -   (g) a C₃₋₆ cycloalkyloxy group,        -   (h) a C₆₋₁₀ aryloxy group,        -   (i) a 5- or 6-membered unsaturated heterocyclyloxy group,        -   (j) a 5- or 6-membered saturated heterocyclyloxy group, and        -   (k) an amino group optionally mono- or di-substituted by            substituents selected from            -   (i) a C₁₋₆ alkyl group,            -   (ii) a C₁₋₆ alkyl-carbonyl group optionally substituted                by 1 to 3 substituents selected from a hydroxy group and                a C₁₋₆ alkoxy group,            -   (iii) a C₁₋₆ alkoxy-carbonyl group optionally                substituted by C₆₋₁₀ aryl group(s), and            -   (iv) a C₃₋₆ cycloalkyl-carbonyl group optionally                substituted by C₁₋₆ alkoxy group(s),    -   (2) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀ aryl        group(s),    -   (3) a C₃₋₆ cycloalkyl group optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group, and        -   (b) a C₁₋₆ alkoxy group,        -   (4) a C₆₋₁₀ aryl group optionally substituted by C₁₋₆ alkyl            group(s) optionally substituted by 1 to 3 halogen atoms,        -   (5) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s) optionally substituted by C₆₋₁₀ aryl            group(s),    -   (6) a 5- or 6-membered unsaturated heterocyclic group optionally        substituted by C₁₋₆ alkyl group(s),    -   (7) a 5- or 6-membered saturated heterocyclic group optionally        substituted by 1 to 3 substituents selected from        -   (a) a C₁₋₆ alkyl group,        -   (b) a C₁₋₆ alkyl-carbonyl group, and        -   (c) an oxo group,    -   (8) a C₃₋₆ cycloalkyloxy group, or    -   (9) a C₆₋₁₀ aryl-carbonyl group, or    -   R^(7″) and R^(8′) form, together with the nitrogen atom and        carbon atom they are bonded to, a 5- or 6-membered cyclic amine        substituted by an oxo group and optionally further substituted        by 1 to 3 substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkyl group optionally substituted by hydroxy            group(s),        -   (c) a C₁₋₆ alkoxy group, and        -   (d) a C₃₋₆ cycloalkyl group.            [2′] A compound represented by the following formula [I′-a]            or a pharmaceutically acceptable salt thereof, or a solvate            thereof:

wherein,

R^(1′) is

(1) a hydrogen atom,(2) a hydroxy group, or(3) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀ aryl group(s);R^(2′) and R^(3′) are the same or different and each is(1) a hydrogen atom, or(2) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a hydroxy group, and    -   (b) a C₁₋₆ alkoxy group;        R^(7′) is a C₁₋₆ alkyl group optionally substituted by 1 to 3        substituents selected from    -   (a) a hydroxy group,    -   (b) a C₁₋₆ alkoxy group, and    -   (c) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s), and

R⁸ is

(1) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from

-   -   (a) a hydroxy group,    -   (b) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀ aryl        group(s),    -   (c) a C₃₋₆ cycloalkyl group optionally substituted by C₁₋₆        alkoxy group(s),    -   (d) a C₆₋₁₀ aryl group,    -   (e) a 5- or 6-membered unsaturated heterocyclic group optionally        substituted by oxo group(s),    -   (f) a 5- to 8-membered saturated heterocyclic group optionally        substituted by 1 to 3 substituents selected from        -   (i) a hydroxy group,        -   (ii) a C₁₋₆ alkyl group optionally substituted by 1 to 3            substituents selected from a hydroxy group and a C₁₋₆ alkoxy            group,        -   (iii) a C₁₋₆ alkoxy group, and        -   (iv) an oxo group,    -   (g) a C₃₋₆ cycloalkyloxy group,    -   (h) a C₆₋₁₀ aryloxy group,    -   (i) a 5- or 6-membered unsaturated heterocyclyloxy group,    -   (j) a 5- or 6-membered saturated heterocyclyloxy group, and    -   (k) an amino group optionally mono- or di-substituted by        substituents selected from        -   (i) a C₁₋₆ alkyl group,        -   (ii) a C₁₋₆ alkyl-carbonyl group optionally substituted by 1            to 3 substituents selected from a hydroxy group and a C₁₋₆            alkoxy group,        -   (iii) a C₁₋₆ alkoxy-carbonyl group optionally substituted by            C₆₋₁₀ aryl group(s), and        -   (iv) a C₃₋₆ cycloalkyl-carbonyl group optionally substituted            by C₁₋₆ alkoxy group(s),            (2) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀aryl            group(s),            (3) a C₃₋₆ cycloalkyl group optionally substituted by 1 to 3            substituents selected from    -   (a) a hydroxy group, and    -   (b) a C₁₋₆ alkoxy group,        (4) a C₆₋₁₀ aryl group optionally substituted by C₁₋₆ alkyl        group(s) optionally substituted by 1 to 3 halogen atoms,        (5) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) optionally substituted by C₆₋₁₀ aryl group(s),        (6) a 5- or 6-membered unsaturated heterocyclic group optionally        substituted by C₁₋₆ alkyl group(s),        (7) a 5- or 6-membered saturated heterocyclic group optionally        substituted by 1 to 3 substituents selected from    -   (a) a C₁₋₆ alkyl group,    -   (b) a C₁₋₆ alkyl-carbonyl group, and    -   (c) an oxo group,        (8) a C₃₋₆ cycloalkyloxy group, or        (9) a C₆₋₁₀ aryl-carbonyl group, or R^(7′″) and R^(8′) form,        together with the nitrogen atom and carbon atom they are bonded        to, a 5- or 6-membered cyclic amine substituted by an oxo group        and optionally further substituted by 1 to 3 substituents        selected from    -   (a) a hydroxy group,    -   (b) a C₁₋₆ alkyl group optionally substituted by hydroxy        group(s),    -   (c) a C₁₋₆ alkoxy group, and    -   (d) a C₃₋₆ cycloalkyl group.        [3′] A pharmaceutical composition comprising the compound        according to the above-mentioned [1′] or [2′], or a        pharmaceutically acceptable salt thereof, or a solvate thereof,        and a pharmaceutically acceptable carrier.        [4′] An agent for the treatment or prophylaxis of an        inflammatory disease, comprising the compound according to the        above-mentioned [1′] or [2′], or a pharmaceutically acceptable        salt thereof, or a solvate thereof.        [5′] An ITK inhibitor comprising the compound according to the        above-mentioned [1′] or [2′], or a pharmaceutically acceptable        salt thereof, or a solvate thereof.        [6′] An agent for the treatment or prophylaxis of an allergic        disease, comprising the compound according to the        above-mentioned [1′] or [2′], or a pharmaceutically acceptable        salt thereof, or a solvate thereof.        [7′] An agent for the treatment or prophylaxis of an autoimmune        disease, comprising the compound according to the        above-mentioned [1′] or [2′], or a pharmaceutically acceptable        salt thereof, or a solvate thereof.        [8′] An inhibitor of rejection in transplantation, comprising        the compound according to the above-mentioned [1′] or [2′], or a        pharmaceutically acceptable salt thereof, or a solvate thereof.        [9′] A method for treating or preventing an inflammatory disease        in a mammal, comprising administering a pharmaceutically        effective amount of the compound according to the        above-mentioned [1′] or [2′], or a pharmaceutically acceptable        salt thereof, or a solvate thereof to the mammal.        [10′] A method for treating or preventing an allergic disease in        a mammal, comprising administering a pharmaceutically effective        amount of the compound according to the above-mentioned [1′] or        [2′], or a pharmaceutically acceptable salt thereof, or a        solvate thereof to the mammal.        [11′] A method for treating or preventing an autoimmune disease        in a mammal, comprising administering a pharmaceutically        effective amount of the compound according to the        above-mentioned [1′] or [2′], or a pharmaceutically acceptable        salt thereof, or a solvate thereof to the mammal.        [12′] A method for suppressing rejection in transplantation in a        mammal, comprising administering a pharmaceutically effective        amount of the compound according to the above-mentioned [1′] or        [2′], or a pharmaceutically acceptable salt thereof, or a        solvate thereof, to the mammal.        [13′] Use of the compound according to the above-mentioned [1′]        or [2′], or a pharmaceutically acceptable salt thereof, or a        solvate thereof for producing an agent for the treatment or        prophylaxis of an inflammatory disease.

Effect of the Invention

The indole compound of the present invention effectively inhibits ITKactivity, suppresses growth and activation of Th2 cell, and/orsuppresses activation of mast cells. Therefore, it is effective as anagent for the treatment or prophylaxis of diseases involving growth oractivation of Th2 cell or activation of mast cells, for example,allergic diseases, inflammatory diseases and autoimmune diseases, or asan inhibitor of rejection in transplantation.

EMBODIMENT OF INVENTION

The present invention is explained in detail in the following.

The definition of the term used in the present specification is asfollows.

The “optionally substituted” includes both substitution and withoutsubstitution (no substitution) at substitutable position of an objectgroup. Here, the “no substitution” means that all substitutablepositions of an object group are each a hydrogen atom.

Examples of the “halogen atom” include a fluorine atom, a chlorine atom,a bromine atom and an iodine atom.

The “C₁₋₆ alkyl group” means a straight chain or branched chainsaturated hydrocarbon group having 1 to 6 carbon atoms, and examplesthereof include a methyl group, an ethyl group, a propyl group, anisopropyl group, a butyl group, an isobutyl group, a sec-butyl group, atert-butyl group, a pentyl group, an isopentyl group, a neopentyl group,a 1,2-dimethylpropyl group, a 1-ethylpropyl group, a hexyl group, anisohexyl group, a 1,2,2-trimethylpropyl group, a 1,1-dimethylbutylgroup, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a2-ethylbutyl group and the like.

The “C₁₋₆ alkoxy group” means a hydroxyl group substituted by theabove-mentioned “C₁₋₆ alkyl group”, and examples thereof include amethoxy group, an ethoxy group, a propoxy group, an isopropoxy group, abutoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxygroup, a pentyloxy group, an isopentyloxy group, a neopentyloxy group, a1,2-dimethylpropyloxy group, a 1-ethylpropyloxy group, a hexyloxy group,an isohexyloxy group, a 1,2,2-trimethylpropyloxy group, a1,1-dimethylbutyloxy group, a 2,2-dimethylbutyloxy group, a3,3-dimethylbutyloxy group, a 2-ethylbutyloxy group and the like.

The “C₃₋₆ cycloalkyl group” means a monocyclic saturated hydrocarbongroup having 3 to 6 carbon atoms, and examples thereof include acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup and the like

The “C₃₋₆ cycloalkyloxy group” means a hydroxy group substituted by theabove-mentioned “C₃₋₆ cycloalkyl group”, and examples thereof include acyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, acyclohexyloxy group and the like.

The “C₆₋₁₀ aryl group” means an aromatic hydrocarbon group having 6 to10 carbon atoms, and examples thereof include a phenyl group, a1-naphthyl group, a 2-naphthyl group and the like. Preferred is a phenylgroup.

The “C₆₋₁₀ aryloxy group” means a hydroxy group substituted by theabove-mentioned “C₁₋₁₀aryl group”, and examples thereof include aphenoxy group, a 1-naphthyloxy group, a 2-naphthyloxy group and thelike. Preferred is a phenoxy group.

The “5- or 6-membered unsaturated heterocyclic group” means a monocyclicunsaturated or partially unsaturated heterocyclic group having 5 or 6ring-constituting atoms, which contains, besides carbon atoms, 1 to 4hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom. When the group contains a sulfur atom as a hetero atom, the sulfuratom is optionally mono- or di-oxidized. Examples of such group includea furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, anoxazolinyl group, an isoxazolyl group, an isoxazolinyl group, athiazolyl group, a thiazolinyl group, an isothiazolyl group, anisothiazolinyl group, an imidazolyl group, an imidazolinyl group, apyrazolyl group, a pyrazolinyl group, an oxadiazolyl group(1,2,5-oxadiazolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolylgroup), a thiadiazolyl group (1,2,5-thiadiazolyl group,1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group), a triazolyl group(1,2,3-triazolyl group, 1,2,4-triazolyl group), a tetrazolyl group, apyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinylgroup, a triazinyl group, a dihydropyridyl group and the like.

The “5- or 6-membered unsaturated heterocyclyloxy group” means a hydroxygroup substituted by the above-mentioned “5- or 6-membered unsaturatedheterocyclic group”, and examples thereof include a furyloxy group, athienyloxy group, a pyrrolyloxy group, an oxazolyloxy group, anoxazolinyloxy group, an isoxazolyloxy group, an isoxazolinyloxy group, athiazolyloxy group, a thiazolinyloxy group, an isothiazolyloxy group, anisothiazolinyloxy group, an imidazolyloxy group, an imidazolinyloxygroup, a pyrazolyloxy group, a pyrazolinyloxy group, an oxadiazolyloxygroup (1,2,5-oxadiazolyloxy group, 1,3,4-oxadiazolyloxy group,1,2,4-oxadiazolyloxy group), a thiadiazolyloxy group(1,2,5-thiadiazolyloxy group, 1,3,4-thiadiazolyloxy group,1,2,4-thiadiazolyloxy group), a triazolyloxy group (1,2,3-triazolyloxygroup, 1,2,4-triazolyloxy group), a tetrazolyloxy group, a pyridyloxygroup, a pyrimidinyloxy group, a pyridazinyloxy group, a pyrazinyloxygroup, a triazinyloxy group, a dihydropyridyloxy group and the like.

The “5- to 8-membered saturated heterocyclic group” means a monocyclicsaturated heterocyclic group having 5 to 8 ring-constituting atoms,which contains, besides carbon atoms, 1 to 4 hetero atoms selected froma nitrogen atom, an oxygen atom and a sulfur atom. When the groupcontains a sulfur atom as a hetero atom, the sulfur atom is optionallymono- or di-oxidized. Examples of such group include a pyrrolidinylgroup, a tetrahydrofuryl group, a tetrahydropyranyl group, atetrahydrothienyl group, a tetrahydrothiopyranyl group, an oxazolidinylgroup, an isoxazolidinyl group, a thiazolidinyl group, anisothiazolidinyl group, an imidazolidinyl group, a pyrazolidinyl group,a piperidyl group (including piperidino group), a morpholinyl group(including morpholino group), a thiomorpholinyl group (includingthiomorpholino group), a piperazinyl group, an azepanyl group, anazocanyl group, a 1,1-dioxideisothiazolidinyl group, a1,1-dioxidetetrahydrothienyl group, a 1,1-dioxidetetrahydrothiopyranylgroup, a 1,1-dioxidethiomorpholinyl group (including1,1-dioxidethiomorpholino group) and the like.

The “5- or 6-membered saturated heterocyclic group” means, among theabove-mentioned “5- to 8-membered saturated heterocyclic groups”, agroup having 5 or 6 ring-constituting atoms, and examples thereofinclude a pyrrolidinyl group, a tetrahydrofuryl group, atetrahydropyranyl group, a tetrahydrothienyl group, atetrahydrothiopyranyl group, an oxazolidinyl group, an isoxazolidinylgroup, a thiazolidinyl group, an isothiazolidinyl group, animidazolidinyl group, a pyrazolidinyl group, a piperidyl group(including piperidino group), a morpholinyl group (including morpholinogroup), a thiomorpholinyl group (including thiomorpholino group), apiperazinyl group, a 1,1-dioxideisothiazolidinyl group, a1,1-dioxidetetrahydrothienyl group, a 1,1-dioxidetetrahydrothiopyranylgroup, a 1,1-dioxidethiomorpholinyl group (including1,1-dioxidethiomorpholino group) and the like.

The “5- or 6-membered saturated heterocyclyloxy group” means a hydroxygroup substituted by the above-mentioned “5- or 6-membered saturatedheterocyclic group”, and examples thereof include a pyrrolidinyloxygroup, a tetrahydrofuryloxy group, a tetrahydropyranyloxy group, atetrahydrothienyloxy group, a tetrahydrothiopyranyloxy group, anoxazolidinyloxy group, an isoxazolidinyloxy group, a thiazolidinyloxygroup, an isothiazolidinyloxy group, an imidazolidinyloxy group, apyrazolidinyloxy group, a piperidyloxy group (including piperidinooxygroup), a morpholinyloxy group (including morpholinooxy group), athiomorpholinyloxy group (including thiomorpholinooxy group), apiperazinyloxy group, a 1,1-dioxideisothiazolidinyloxy group, a1,1-dioxidetetrahydrothienyloxy group, a1,1-dioxidetetrahydrothiopyranyloxy group, a1,1-dioxidethiomorpholinyloxy group (including1,1-dioxidethiomorpholinooxy group) and the like.

The “C₁₋₆ alkyl-carbonyl group” means a carbonyl group to which theabove-mentioned “C₁₋₆ alkyl group” is bonded, and examples thereofinclude an acetyl group, a propanoyl group, a butanoyl group, a2-methylpropanoyl group, a 2,2-dimethylpropanoyl group, a3-methylbutanoyl group and the like.

The “C₁₋₆ alkoxy-carbonyl group” means a carbonyl group to which theabove-mentioned “C₁₋₆ alkoxy group” is bonded, and examples thereofinclude a methoxycarbonyl group, an ethoxycarbonyl group, apropoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonylgroup, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, atert-butoxycarbonyl group, a pentyloxycarbonyl group, anisopentyloxycarbonyl group, a neopentyloxycarbonyl group, ahexyloxycarbonyl group and the like.

The “C₃₋₆ cycloalkyl-carbonyl group” means a carbonyl group to which theabove-mentioned “C₃₋₆ cycloalkyl group” is bonded, and examples thereofinclude a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, acyclopentylcarbonyl group, a cyclohexylcarbonyl group and the like.

The “C₆₋₁₀ aryl-carbonyl group” means a carbonyl group to which theabove-mentioned “C₆₋₁₀ aryl group” is bonded, and examples thereofinclude a benzoyl group and the like.

The “carboxy-C₁₋₆ alkoxy group” means the above-mentioned “C₁₋₆ alkoxygroup” to which a carboxy group is bonded, and examples thereof includea carboxymethoxy group, a 2-carboxyethoxy group, a 3-carboxypropoxygroup, a 2-carboxy-1-methylethoxy group, a 4-carboxybutoxy group and thelike. Preferred is a carboxymethoxy group.

The “5- or 6-membered cyclic amine” means a saturated heterocycle having5 or 6 ring-constituting atoms, which contains at least one nitrogenatom besides carbon atoms, further optionally contains 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom,which is bonded via the nitrogen atom constituting the ring. When thering contains a sulfur atom as a hetero atom, the sulfur atom isoptionally mono- or di-oxidized. Examples of such ring includepyrrolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,imidazolidine, pyrazolidine, piperidine, morpholine, thiomorpholine,piperazine, 1,1-dioxideisothiazolidine, 1,1-dioxidethiomorpholine andthe like.

The “5- or 6-membered unsaturated heterocycle” means a monocyclicunsaturated or partially unsaturated heterocyclic group having 5 or 6ring-constituting atoms, which contains, besides carbon atoms, 1 to 4hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfuratom. When the ring contains a sulfur atom as a hetero atom, the sulfuratom is optionally mono- or di-oxidized. Examples of such ring includefuran, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole,imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole,pyridine, pyrimidine, pyridazine, pyrazine, triazine and the like.

Each group of a compound represented by the formula [I](hereinaftersometimes to be abbreviated as compound [I]) is explained in thefollowing.

R¹ is

(1) a hydrogen atom,(2) a hydroxy group, or(3) a C₁₋₆ alkoxy group (preferably, a methoxy group, an isopropoxygroup) optionally substituted by C₆₋₁₀ aryl group(s) (preferably, aphenyl group),and preferably a hydrogen atom.

R² and R³ are the same or different and each is

(1) a hydrogen atom, or(2) a C₁₋₆ alkyl group (preferably, a methyl group) optionallysubstituted by 1 to 3 substituents selected from

-   -   (a) a hydroxy group, and    -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group), and are        preferably the same or different and each is a C₁₋₆ alkyl group        (preferably, a methyl group).

R⁴ is a group represented by

which is bonded to the 5-position or the 6-position of the indole ring.

R⁴ is preferably

which is bonded to the 5-position or the 6-position of the indole ring,or

which is bonded to the 6-position of the indole ring, and morepreferably

which is bonded to the 6-position of the indole ring.

R⁵ is

(1) a hydrogen atom, or(2) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl group).

R⁶ is

(1) a hydrogen atom,(2) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl group, anisopropyl group, an isobutyl group, a tert-butyl group, a neopentylgroup, a 1,2-dimethylpropyl group, a 1,2,2-trimethylpropyl group)optionally substituted by 1 to 3 substituents selected from

(a) a hydroxy group,

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group, a propoxy group,an isopropoxy group),

(c) a carboxy group,

(d) a C₁₋₆ alkoxy-carbonyl group (preferably, a methoxycarbonyl group, atert-butoxycarbonyl group),

(e) a C₆₋₁₀ aryl group (preferably, a phenyl group),

(f) a C₆₋₁₀ aryloxy group (preferably, a phenoxy group),

(g) an amino group optionally mono- or di-substituted C₁₋₆ alkyl groups(preferably, a methyl group),

(h) a 5- or 6-membered unsaturated heterocyclic group (preferably, afuryl group, a pyrrolyl group, a thiazolyl group, a tetrazolyl group, animidazolyl group) optionally substituted by C₁₋₆ alkyl group(s)(preferably, a methyl group), and

(i) a 5- or 6-membered saturated heterocyclic group (preferably, amorpholinyl group),

(3) a C₁₋₆ alkoxy group (preferably, a methoxy group),(4) a C₆₋₁₀ aryl group (preferably, a phenyl group), or(5) a 5- or 6-membered unsaturated heterocyclic group (preferably, a1,3,4-thiadiazolyl group) optionally substituted by 1 to 3 substituentsselected from

(a) a hydroxy group, and

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group).

Alternatively, R⁵ and R⁶ may form, together with the nitrogen atom theyare bonded to, a 5- or 6-membered cyclic amine (preferably, pyrrolidine,piperidine, piperazine, morpholine) (said cyclic amine is optionallycondensed with a 5- or 6-membered unsaturated heterocycle (preferably,imidazole)), which is optionally substituted by 1 to 3 substituentsselected from

(a) a hydroxy group,

(b) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl group),

(c) a C₁₋₆ alkoxy group (preferably, a methoxy group), and

(d) a C₁₋₆ alkoxy-carbonyl group (preferably, a tert-butoxycarbonylgroup).

R⁷ is

(1) a hydrogen atom, or

(2) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl group, apropyl group) optionally substituted by 1 to 3 substituents selectedfrom

(a) a hydroxy group,

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group), and

(c) an amino group optionally mono- or di-substituted by C₁₋₆ alkylgroup(s) (preferably, a methyl group), preferably a C₁₋₆ alkyl group(preferably, a methyl group, an ethyl group, a propyl group) optionallysubstituted by 1 to 3 substituents selected from

(a) a hydroxy group,

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group), and

(c) an amino group optionally mono- or di-substituted by C₁₋₆ alkylgroup(s) (preferably, a methyl group), and more preferably a C₁₋₆ alkylgroup (preferably, a methyl group, an ethyl group, a propyl group).

R⁸ is

(1) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl group, apropyl group, an isopropyl group, an isobutyl group, a tert-butyl group,a neopentyl group) optionally substituted by 1 to 3 substituentsselected from

(a) a hydroxy group,

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group, an ethoxy group, apropoxy group, an isopropoxy group) optionally substituted by C₆₋₁₀ arylgroup(s) (preferably, a phenyl group),

(c) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl group, acyclohexyl group) optionally substituted by C₁₋₆ alkoxy group(s)(preferably, a methoxy group),

(d) a C₆₋₁₀ aryl group (preferably, a phenyl group),

(e) a 5- or 6-membered unsaturated heterocyclic group (preferably, animidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionallysubstituted by oxo group(s),

(f) a 5- to 8-membered saturated heterocyclic group (preferably, atetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group,a piperidyl group, an azepanyl group, an azocanyl group, a morpholinylgroup (including a morpholino group), a 1,1-dioxideisothiazolidinylgroup, an oxazolidinyl group, an imidazolidinyl group) optionallysubstituted by 1 to 3 substituents selected from

-   -   (i) a hydroxy group,    -   (ii) a C₁₋₆ alkyl group (preferably, a methyl group) optionally        substituted by 1 to 3 substituents selected from a hydroxy group        and a C₁₋₆ alkoxy group (preferably, a methoxy group),    -   (iii) a C₁₋₆ alkoxy group (preferably, a methoxy group), and    -   (iv) an oxo group,

(g) a C₃₋₆ cycloalkyloxy group (preferably, a cyclopentyloxy group),

(h) a C₆₋₁₀aryloxy group (preferably, a phenoxy group),

(i) a 5- or 6-membered unsaturated heterocyclyloxy group (preferably, apyridyloxy group),

(j) a 5- or 6-membered saturated heterocyclyloxy group (preferably, atetrahydrofuryloxy group, a tetrahydropyranyloxy group), and

(k) an amino group optionally mono- or di-substituted by substituentsselected from

-   -   (i) a C₁₋₆ alkyl group (preferably, a methyl group) optionally        substituted by 1 to 3 substituents selected from a hydroxy        group, a carboxy group and a carboxy-C₁₋₆ alkoxy group        (preferably, a carboxymethoxy group),    -   (ii) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl group, a        propanoyl group, a 2-methylpropanoyl group, a        2,2-dimethylpropanoyl group, a 3-methylbutanoyl group)        optionally substituted by 1 to 3 substituents selected from a        hydroxy group and a C₁₋₆ alkoxy group (preferably, a methoxy        group),    -   (iii) a C₁₋₆ alkoxy-carbonyl group (preferably, a        methoxycarbonyl group, a tert-butoxycarbonyl group) optionally        substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl group),        and    -   (iv) a C₃₋₆ cycloalkyl-carbonyl group (preferably, a        cyclopropylcarbonyl group, a cyclohexylcarbonyl group)        optionally substituted by C₁₋₆ alkoxy group(s) (preferably, a        methoxy group),        (2) a C₁₋₆ alkoxy group (preferably, a methoxy group) optionally        substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl group),        (3) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl group,        cyclohexyl group) optionally substituted by 1 to 3 substituents        selected from

(a) a hydroxy group, and

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group),

(4) a C₆₋₁₀ aryl group (preferably, a phenyl group) optionallysubstituted by C₁₋₆ alkyl group(s) (preferably, a methyl group)optionally substituted by 1 to 3 halogen atoms (preferably, a fluorineatom),(5) an amino group optionally mono- or di-substituted by C₁₋₆ alkylgroup(s) (preferably, a methyl group) optionally substituted by C₆₋₁₀aryl group(s) (preferably, a phenyl group),(6) a 5- or 6-membered unsaturated heterocyclic group (preferably, anisoxazolyl group) optionally substituted by C₁₋₆ alkyl group(s)(preferably, a methyl group),(7) a 5- or 6-membered saturated heterocyclic group (preferably, atetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group,a piperidyl group) optionally substituted by 1 to 3 substituentsselected from

(a) a C₁₋₆ alkyl group (preferably, a methyl group),

(b) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl group), and

(c) an oxo group,

(8) a C₃₋₆ cycloalkyloxy group (preferably, a cyclohexyloxy group), or(9) a C₆₋₁₀ aryl-carbonyl group (preferably, a benzoyl group).

R⁸ is preferably a C₁₋₆ alkyl group (preferably, a methyl group, anethyl group, a propyl group, an isopropyl group, an isobutyl group, atert-butyl group, a neopentyl group) substituted by 1 to 3 substituentsselected from

(a) a hydroxy group,

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group, an ethoxy group, apropoxy group, an isopropoxy group) optionally substituted by C₆₋₁₀ arylgroup(s) (preferably, a phenyl group),

(c) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl group, acyclohexyl group) optionally substituted by C₁₋₆ alkoxy group(s)(preferably, a methoxy group),

(d) a C₆₋₁₀ aryl group (preferably, phenyl group),

(e) a 5- or 6-membered unsaturated heterocyclic group (preferably, animidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionallysubstituted by oxo group(s),

(f) a 5- to 8-membered saturated heterocyclic group (preferably, atetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group,a piperidyl group, an azepanyl group, an azocanyl group, a morpholinylgroup (including a morpholino group), 1,1-dioxideisothiazolidinyl group,an oxazolidinyl group, an imidazolidinyl group) optionally substitutedby 1 to 3 substituents selected from

-   -   (i) a hydroxy group,    -   (ii) a C₁₋₆ alkyl group (preferably, a methyl group) optionally        substituted by 1 to 3 substituents selected from a hydroxy group        and a C₁₋₆ alkoxy group (preferably, a methoxy group),    -   (iii) a C₁₋₆ alkoxy group (preferably, a methoxy group), and    -   (iv) an oxo group,

(g) a C₃₋₆ cycloalkyloxy group (preferably, a cyclopentyloxy group),

(h) a C₆₋₁₀ aryloxy group (preferably, a phenoxy group),

(i) a 5- or 6-membered unsaturated heterocyclyloxy group (preferably, apyridyloxy group),

(j) a 5- or 6-membered saturated heterocyclyloxy group (preferably, atetrahydrofuryloxy group, a tetrahydropyranyloxy group), and

(k) an amino group optionally mono- or di-substituted by substituentsselected from

-   -   (i) a C₁₋₆ alkyl group (preferably, a methyl group) optionally        substituted by 1 to 3 substituents selected from a hydroxy        group, a carboxy group and a carboxy-C₁₋₆ alkoxy group        (preferably, a carboxymethoxy group),    -   (ii) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl group,        propanoyl group, a 2-methylpropanoyl group, a        2,2-dimethylpropanoyl group, a 3-methylbutanoyl group)        optionally substituted by 1 to 3 substituents selected from a        hydroxy group and a C₁₋₆ alkoxy group (preferably, a methoxy        group),    -   (iii) a C₁₋₆ alkoxy-carbonyl group (preferably, a        methoxycarbonyl group, a tert-butoxycarbonyl group) optionally        substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl group),        and    -   (iv) a C₃₋₆ cycloalkyl-carbonyl group (preferably, a        cyclopropylcarbonyl group, a cyclohexylcarbonyl group)        optionally substituted by C₁₋₆ alkoxy group(s) (preferably, a        methoxy group).

R⁸ is more preferably a C₁₋₆ alkyl group (preferably, a methyl group, anethyl group, propyl group, an isopropyl group) substituted by 1 to 3substituents selected from

(c) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl group, acyclohexyl group) optionally substituted by C₁₋₆ alkoxy group(s)(preferably, a methoxy group),

(d) a C₆₋₁₀ aryl group (preferably, a phenyl group),

(e) a 5- or 6-membered unsaturated heterocyclic group (preferably, animidazolyl group, a dihydropyridyl group, pyrazolyl group) optionallysubstituted by oxo group(s), and

(f) a 5- to 8-membered saturated heterocyclic group (preferably, amorpholinyl group (including a morpholino group)) optionally substitutedby 1 to 3 substituents selected from

-   -   (i) a hydroxy group,    -   (ii) a C₁₋₆ alkyl group (preferably, a methyl group) optionally        substituted by 1 to 3 substituents selected from a hydroxy group        and a C₁₋₆ alkoxy group (preferably, a methoxy group),    -   (iii) a C₁₋₆ alkoxy group (preferably, a methoxy group), and    -   (iv) an oxo group.

R⁸ is particularly preferably a C₁₋₆ alkyl group (preferably, a methylgroup, an ethyl group) substituted by 5- to 8-membered saturatedheterocyclic group(s) (preferably, a morpholino group) optionallysubstituted by 1 to 3 substituents selected from

(i) a hydroxy group,

(ii) a C₁₋₆ alkyl group (preferably, a methyl group) optionallysubstituted by 1 to 3 substituents selected from a hydroxy group and aC₁₋₆ alkoxy group (preferably, a methoxy group),

(iii) a C₁₋₆ alkoxy group (preferably, a methoxy group), and

(iv) an oxo group.

Alternatively, R⁷ and R⁸ may form, together with the nitrogen atom andcarbon atom they are bonded to, a 5- or 6-membered cyclic aminesubstituted by an oxo group (preferably, 2-oxopyrrolidine,2-oxopiperidine, 2-oxooxazolidine) and optionally further substituted by1 to 3 substituents selected from

(a) a hydroxy group,

(b) a C₁₋₆ alkyl group (preferably, methyl group) optionally substitutedby a hydroxy group,

(c) a C₁₋₆ alkoxy group (preferably, methoxy group), and

(d) a C₃₋₆ cycloalkyl group (preferably, cyclohexyl group).

As Compound [I], a compound wherein

R¹ is

(1) a hydrogen atom,(2) a hydroxy group, or(3) a C₁₋₆ alkoxy group (preferably, a methoxy group, an isopropoxygroup) optionally substituted by C₆₋₁₀ aryl group(s) (preferably, aphenyl group);R² and R³ are the same or different and each is(1) a hydrogen atom, or(2) a C₁₋₆ alkyl group (preferably, a methyl group) optionallysubstituted by 1 to 3 substituents selected from

(a) a hydroxy group, and

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group); and R⁴ is

which is bonded to the 5-position or the 6-position of the indole ring,or

which is bonded to the 6-position of the indole ring (preferably,

which is bonded to the 6-position of the indole ring),

-   -   wherein    -   R⁵ is    -   (1) a hydrogen atom, or    -   (2) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl        group), and    -   R⁶ is    -   (1) a hydrogen atom,    -   (2) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl        group, an isopropyl group, an isobutyl group, a tert-butyl        group, a neopentyl group, a 1,2-dimethylpropyl group, a        1,2,2-trimethylpropyl group) optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group, a            propoxy group, an isopropoxy group),        -   (c) a carboxy group,        -   (d) a C₁₋₆ alkoxy-carbonyl group (preferably, a            methoxycarbonyl group, a tert-butoxycarbonyl group),        -   (e) a C₆₋₁₀ aryl group (preferably, phenyl group),        -   (f) a C₆₋₁₀ aryloxy group (preferably, a phenoxy group),        -   (g) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s) (preferably, a methyl group),        -   (h) a 5- or 6-membered unsaturated heterocyclic group            (preferably, a furyl group, a pyrrolyl group, a thiazolyl            group, a tetrazolyl group, an imidazolyl group) optionally            substituted by C₁₋₆ alkyl group(s) (preferably, a methyl            group), and        -   (i) a 5- or 6-membered saturated heterocyclic group            (preferably, a morpholinyl group),    -   (3) a C₁₋₆ alkoxy group (preferably, a methoxy group),    -   (4) a C₆₋₁₀ aryl group (preferably, a phenyl group), or    -   (5) a 5- or 6-membered unsaturated heterocyclic group        (preferably, a 1,3,4-thiadiazolyl group) optionally substituted        by 1 to 3 substituents selected from        -   (a) a hydroxy group, and        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group), or    -   R⁵ and R⁶ form, together with the nitrogen atom they are bonded        to, a 5- or 6-membered cyclic amine (preferably, pyrrolidine,        piperidine, piperazine, morpholine) (said cyclic amine is        optionally condensed with 5- or 6-membered unsaturated        heterocycle (preferably, imidazole)) optionally substituted by 1        to 3 substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl            group),        -   (c) a C₁₋₆ alkoxy group (preferably, a methoxy group), and        -   (d) a C₁₋₆ alkoxy-carbonyl group (preferably, a            tert-butoxycarbonyl group);

R⁷ is

-   -   (1) a hydrogen atom, or    -   (2) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl        group, a propyl group) optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group), and        -   (c) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s) (preferably, a methyl group)            [preferably,    -   a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl group,        propyl group) optionally substituted by 1 to 3 substituents        selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group), and        -   (c) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s) (preferably, a methyl group)], and R⁸ is    -   (1) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl        group, a propyl group, an isopropyl group, an isobutyl group, a        tert-butyl group, a neopentyl group) optionally substituted by 1        to 3 substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group, an            ethoxy group, a propoxy group, an isopropoxy group)            optionally substituted by C₆₋₁₀ aryl group(s) (preferably, a            phenyl group),        -   (c) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl            group, a cyclohexyl group) optionally substituted by C₁₋₆            alkoxy group(s) (preferably, a methoxy group),        -   (d) a C₆₋₁₀ aryl group (preferably, a phenyl group),        -   (e) a 5- or 6-membered unsaturated heterocyclic group            (preferably, an imidazolyl group, a dihydropyridyl group, a            pyrazolyl group) optionally substituted by oxo group(s),        -   (f) a 5- to 8-membered saturated heterocyclic group            (preferably, a tetrahydrofuryl group, a tetrahydropyranyl            group, a pyrrolidinyl group, a piperidyl group, an azepanyl            group, an azocanyl group, a morpholinyl group (including a            morpholino group), a 1,1-dioxideisothiazolidinyl group,            oxazolidinyl group, an imidazolidinyl group) optionally            substituted by 1 to 3 substituents selected from            -   (i) a hydroxy group,            -   (ii) a C₁₋₆ alkyl group (preferably, a methyl group)                optionally substituted by 1 to 3 substituents selected                from a hydroxy group and a C₁₋₆ alkoxy group                (preferably, a methoxy group),            -   (iii) a C₁₋₆ alkoxy group (preferably, a methoxy group),                and            -   (iv) an oxo group,        -   (g) a C₃₋₆ cycloalkyloxy group (preferably, a cyclopentyloxy            group),        -   (h) a C₆₋₁₀ aryloxy group (preferably, a phenoxy group),        -   (i) a 5- or 6-membered unsaturated heterocyclyloxy group            (preferably, a pyridyloxy group),        -   (j) a 5- or 6-membered saturated heterocyclyloxy group            (preferably, a tetrahydrofuryloxy group, a            tetrahydropyranyloxy group), and        -   (k) an amino group optionally mono- or di-substituted by            substituents selected from            -   (i) a C₁₋₆ alkyl group (preferably, a methyl group)                optionally substituted by 1 to 3 substituents selected                from a hydroxy group, a carboxy group and a carboxy-C₋₋₆                is alkoxy group (preferably, a carboxymethoxy group),            -   (ii) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl                group, a propanoyl group, a 2-methylpropanoyl group, a                2,2-dimethylpropanoyl group, a 3-methylbutanoyl group)                optionally substituted by 1 to 3 substituents selected                from a hydroxy group and a C₁₋₆ alkoxy group                (preferably, a methoxy group),            -   (iii) a C₁₋₆ alkoxy-carbonyl group (preferably, a                methoxycarbonyl group, a tert-butoxycarbonyl group)                optionally substituted by C₆₋₁₀ aryl group(s)                (preferably, a phenyl group), and            -   (iv) a C₃₋₆ cycloalkyl-carbonyl group (preferably, a                cyclopropylcarbonyl group, a cyclohexylcarbonyl group)                optionally substituted by C₁₋₆ alkoxy group(s)                (preferably, a methoxy group),    -   (2) a C₁₋₆ alkoxy group (preferably, a methoxy group) optionally        substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl group),    -   (3) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl group,        cyclohexyl group) optionally substituted by 1 to 3 substituents        selected from        -   (a) a hydroxy group, and        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group),    -   (4) a C₆₋₁₀aryl group (preferably, a phenyl group) optionally        substituted by a C₁₋₆ alkyl group (preferably, a methyl group)        optionally substituted by 1 to 3 halogen atoms (preferably, a        fluorine atom),    -   (5) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (preferably, a methyl group) optionally        substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl group),    -   (6) a 5- or 6-membered unsaturated heterocyclic group        (preferably, an isoxazolyl group) optionally substituted by C₁₋₆        alkyl group(s) (preferably, a methyl group),    -   (7) a 5- or 6-membered saturated heterocyclic group (preferably,        a tetrahydrofuryl group, a tetrahydropyranyl group, a        pyrrolidinyl group, a piperidyl group) optionally substituted by        1 to 3 substituents selected from        -   (a) a C₁₋₆ alkyl group (preferably, a methyl group),        -   (b) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl            group), and        -   (c) an oxo group,    -   (8) a C₃₋₆ cycloalkyloxy group (preferably, a cyclohexyloxy        group), or    -   (9) a C₆₋₁₀ aryl-carbonyl group (preferably, a benzoyl group),        or    -   R⁷ and R⁸ form, together with the nitrogen atom and carbon atom        they are bonded to, a 5- or 6-membered cyclic amine substituted        by an oxo group (preferably, 2-oxopyrrolidine, 2-oxopiperidine,        2-oxooxazolidine) and optionally further substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkyl group (preferably, a methyl group)            optionally substituted by hydroxy group(s),        -   (c) a C₁₋₆ alkoxy group (preferably, a methoxy group), and        -   (d) a C₃₋₆ cycloalkyl group (preferably, a cyclohexyl group)            is preferable.

Particularly, a compound wherein

R¹ is

(1) a hydrogen atom,(2) a hydroxy group, or(3) a C₁₋₆ alkoxy group (preferably, a methoxy group, an isopropoxygroup) optionally substituted by C₆₋₁₀ aryl group(s) (preferably, aphenyl group);R² and R³ are the same or different and each is(1) a hydrogen atom, or(2) a C₁₋₆ alkyl group (preferably, a methyl group) optionallysubstituted by 1 to 3 substituents selected from

-   -   (a) a hydroxy group, and    -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group);

R⁴ is

which is bonded to the 6-position of the indole ring,

-   -   wherein    -   R⁷ is a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl        group, a propyl group) optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group), and        -   (c) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s) (preferably, a methyl group), and R⁸ is    -   (1) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl        group, a propyl group, an isopropyl group, an isobutyl group, a        tert-butyl group, a neopentyl group) optionally substituted by 1        to 3 substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group, an            ethoxy group, a propoxy group, an isopropoxy group)            optionally substituted by C₆₋₁₀ aryl group(s) (preferably, a            phenyl group),        -   (c) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl            group, a cyclohexyl group) optionally substituted by C₁₋₆            alkoxy group(s) (preferably, a methoxy group),        -   (d) a C₆₋₁₀ aryl group (preferably, a phenyl group),        -   (e) a 5- or 6-membered unsaturated heterocyclic group            (preferably, an imidazolyl group, a dihydropyridyl group, a            pyrazolyl group) optionally substituted by oxo group(s),        -   (f) a 5- to 8-membered saturated heterocyclic group            (preferably, a tetrahydrofuryl group, a tetrahydropyranyl            group, a pyrrolidinyl group, a piperidyl group, an azepanyl            group, an azocanyl group, a morpholinyl group (including a            morpholino group), a 1,1-dioxideisothiazolidinyl group, an            oxazolidinyl group, imidazolidinyl group) optionally            substituted by 1 to 3 substituents selected from            -   (i) a hydroxy group,            -   (ii) a C₁₋₆ alkyl group (preferably, a methyl group)                optionally substituted by 1 to 3 substituents selected                from a hydroxy group and a C₁₋₆ alkoxy group                (preferably, a methoxy group),            -   (iii) a C₁₋₆ alkoxy group (preferably, a methoxy group),                and            -   (iv) an oxo group,        -   (g) a C₃₋₆ cycloalkyloxy group (preferably, a cyclopentyloxy            group),        -   (h) a C₆₋₁₀ aryloxy group (preferably, a phenoxy group),        -   (i) a 5- or 6-membered unsaturated heterocyclyloxy group            (preferably, a pyridyloxy group),        -   (j) a 5- or 6-membered saturated heterocyclyloxy group            (preferably, a tetrahydrofuryloxy group, a            tetrahydropyranyloxy group), and        -   (k) an amino group optionally mono- or di-substituted by            substituents selected from            -   (i) a C₁₋₆ alkyl group (preferably, a methyl group)                optionally substituted by 1 to 3 substituents selected                from a hydroxy group, a carboxy group and a carboxy-C₁₋₆                alkoxy group (preferably, a carboxymethoxy group),            -   (ii) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl                group, a propanoyl group, a 2-methylpropanoyl group, a                2,2-dimethylpropanoyl group, a 3-methylbutanoyl group)                optionally substituted by 1 to 3 substituents selected                from a hydroxy group and a C₁₋₆ alkoxy group                (preferably, a methoxy group),            -   (iii) a C₁₋₆ alkoxy-carbonyl group (preferably, a                methoxycarbonyl group, a tert-butoxycarbonyl group)                optionally substituted by C₆₋₁₀ aryl group(s)                (preferably, a phenyl group), and            -   (iv) a C₃₋₆ cycloalkyl-carbonyl group (preferably, a                cyclopropylcarbonyl group, a cyclohexylcarbonyl group)                optionally substituted by C₁₋₆ alkoxy group(s)                (preferably, a methoxy group),        -   (2) a C₁₋₆ alkoxy group (preferably, a methoxy group)            optionally substituted by C₆₋₁₀ aryl group(s) (preferably, a            phenyl group),        -   (3) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl            group, a cyclohexyl group) optionally substituted by 1 to 3            substituents selected from            -   (a) a hydroxy group, and            -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group),        -   (4) a C₆₋₁₀ aryl group (preferably, a phenyl group)            optionally substituted by a C₁₋₆ alkyl group (preferably, a            methyl group) optionally substituted by 1 to 3 halogen atoms            (preferably, a fluorine atom),        -   (5) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s) (preferably, a methyl group) optionally            substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl            group),        -   (6) a 5- or 6-membered unsaturated heterocyclic group            (preferably, an isoxazolyl group) optionally substituted by            C₁₋₆ alkyl group(s) (preferably, a methyl group),        -   (7) a 5- or 6-membered saturated heterocyclic group            (preferably, a tetrahydrofuryl group, a tetrahydropyranyl            group, a pyrrolidinyl group, a piperidyl group) optionally            substituted by 1 to 3 substituents selected from            -   (a) a C₁₋₆ alkyl group (preferably, a methyl group),            -   (b) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl                group), and            -   (c) an oxo group,        -   (8) a C₃₋₆ cycloalkyloxy group (preferably, a cyclohexyloxy            group), or        -   (9) a C₆₋₁₀ aryl-carbonyl group (preferably, a benzoyl            group), or        -   R⁷ and R⁸ form, together with the nitrogen atom and carbon            atom they are bonded to, a 5- or 6-membered cyclic amine            substituted by an oxo group (preferably, 2-oxopyrrolidine,            2-oxopiperidine, 2-oxooxazolidine) and optionally further            substituted by 1 to 3 substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkyl group (preferably, a methyl group)            optionally substituted by hydroxy group(s),        -   (c) a C₁₋₆ alkoxy group (preferably, a methoxy group), and        -   (d) a C₃₋₆ cycloalkyl group (preferably, a cyclohexyl            group),            that is, a compound represented by the above-mentioned            formula [I-a] is particularly preferable.

As a compound represented by the formula [I-a], a compound wherein

R¹ is a hydrogen atom;R² and R³ are the same or different and each is a C₁₋₆ alkyl group(preferably, a methyl group);R^(7′) is a C₁₋₆ alkyl group (preferably, a methyl group, an ethylgroup, a propyl group), andR⁸ is a C₁ alkyl group (preferably, a methyl group, an ethyl group, apropyl group, an isopropyl group, an isobutyl group, a tert-butyl group,a neopentyl group) substituted by 1 to 3 substituents selected from

(a) a hydroxy group,

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group, an ethoxy group, apropoxy group, an isopropoxy group) optionally substituted by C₆₋₁₀ arylgroup(s) (preferably, a phenyl group),

(c) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl group, acyclohexyl group) optionally substituted by C₁₋₆ alkoxy group(s)(preferably, a methoxy group),

(d) a C₆₋₁₀ aryl group (preferably, a phenyl group),

(e) a 5- or 6-membered unsaturated heterocyclic group (preferably, animidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionallysubstituted by oxo group(s),

(f) a 5- to 8-membered saturated heterocyclic group (preferably, atetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group,a piperidyl group, an azepanyl group, an azocanyl group, a morpholinylgroup (including a morpholino group), a 1,1-dioxideisothiazolidinylgroup, a oxazolidinyl group, an imidazolidinyl group) optionallysubstituted by 1 to 3 substituents selected from

-   -   (i) a hydroxy group,    -   (ii) a C₁₋₆ alkyl group (preferably, a methyl group) optionally        substituted by 1 to 3 substituents selected from a hydroxy group        and a C₁₋₆ alkoxy group (preferably, a methoxy group),    -   (iii) a C₁₋₆ alkoxy group (preferably, a methoxy group), and    -   (iv) an oxo group,

(g) a C₃₋₆ cycloalkyloxy group (preferably, a cyclopentyloxy group),

(h) a C₆₋₁₀ aryloxy group (preferably, a phenoxy group),

(i) a 5- or 6-membered unsaturated heterocyclyloxy group (preferably, apyridyloxy group),

(j) a 5- or 6-membered saturated heterocyclyloxy group (preferably, atetrahydrofuryloxy group, a tetrahydropyranyloxy group), and

(k) an amino group optionally mono- or di-substituted by substituentsselected from

-   -   (i) a C₁₋₆ alkyl group (preferably, a methyl group) optionally        substituted by 1 to 3 substituents selected from a hydroxy        group, a carboxy group and a carboxy-C₁₋₆ alkoxy group        (preferably, a carboxymethoxy group),    -   (ii) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl group, a        propanoyl group, a 2-methylpropanoyl group, a        2,2-dimethylpropanoyl group, a 3-methylbutanoyl group)        optionally substituted by 1 to 3 substituents selected from a        hydroxy group and a C₁₋₆ alkoxy group (preferably, a methoxy        group),    -   (iii) a C₁₋₆ alkoxy-carbonyl group (preferably, a        methoxycarbonyl group, a tert-butoxycarbonyl group) optionally        substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl group),        and    -   (iv) a C₃₋₆ cycloalkyl-carbonyl group (preferably, a        cyclopropylcarbonyl group, a cyclohexylcarbonyl group)        optionally substituted by C₁₋₆ alkoxy group(s) (preferably, a        methoxy group)        is preferable.

In another embodiment, as compound [I], a compound represented by theabove-mentioned formula [I′] (hereinafter sometimes to be abbreviated ascompound [I′]) is preferable. Each group of compound [I′] is explainedin the following.

R¹ is

(1) a hydrogen atom,(2) a hydroxy group, or(3) a C₁₋₆ alkoxy group (preferably, a methoxy group, an isopropoxygroup) optionally substituted by C₆₋₁₀ aryl group(s) (preferably, aphenyl group).

R^(2′) and R^(3′) are the same or different and each is (1) a hydrogenatom, or

(2) a C₁₋₆ alkyl group (preferably, a methyl group) optionallysubstituted by 1 to 3 substituents selected from

(a) a hydroxy group, and

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group).

R^(4′) is a group represented by

which is bonded to the 5-position or the 6-position of the indole ring.

R^(4′) is preferably

which is bonded to the 5-position or the 6-position of the indole ring,or

which is bonded to the 6-position of the indole ring, more preferably,

which is bonded to the 6-position of the indole ring.

R^(5′) is

(1) a hydrogen atom, or(2) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl group).

R^(6′) is

(1) a hydrogen atom,(2) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl group, anisopropyl group, an isobutyl group, a tert-butyl group, a neopentylgroup, a 1,2-dimethylpropyl group, a 1,2,2-trimethylpropyl group)optionally substituted by 1 to 3 substituents selected from

(a) a hydroxy group,

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group, a propoxy group,an isopropoxy group),

(c) a carboxy group,

(d) a C₁₋₆ alkoxy-carbonyl group (preferably, a methoxycarbonyl group, atert-butoxycarbonyl group),

(e) a C₆₋₁₀ aryl group (preferably, a phenyl group),

(f) a C₆₋₁₀ aryloxy group (preferably, a phenoxy group),

(g) an amino group optionally mono- or di-substituted by C₁₋₆ alkylgroup(s) (preferably, a methyl group),

(h) a 5- or 6-membered unsaturated heterocyclic group (preferably, afuryl group, a pyrrolyl group, a thiazolyl group, a tetrazolyl group, animidazolyl group) optionally substituted by C₁₋₆ alkyl group(s)(preferably, a methyl group), and

(i) a 5- or 6-membered saturated heterocyclic group (preferably, amorpholinyl group),

(3) a C₁₋₆ alkoxy group (preferably, a methoxy group),(4) a C₆₋₁₀ aryl group (preferably, a phenyl group), or(5) a 5- or 6-membered unsaturated heterocyclic group (preferably, a1,3,4-thiadiazolyl group) optionally substituted by 1 to 3 substituentsselected from

(a) a hydroxy group, and

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group).

Alternatively, R^(5′) and R^(6′) may form, together with the nitrogenatom they are bonded to, a 5- or 6-membered cyclic amine (preferably,pyrrolidine, piperidine, piperazine, morpholine) (said cyclic amine isoptionally condensed with 5- or 6-membered unsaturated heterocycle(preferably, imidazole)), which is optionally substituted by 1 to 3substituents selected from

(a) a hydroxy group,

(b) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl group),

(c) a C₁₋₆ alkoxy group (preferably, a methoxy group), and

(d) a C₁₋₆ alkoxy-carbonyl group (preferably, a tert-butoxycarbonylgroup).

R^(7′) is

(1) a hydrogen atom, or(2) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl group, apropyl group) optionally substituted by 1 to 3 substituents selectedfrom

(a) a hydroxy group,

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group), and

(c) an amino group optionally mono- or di-substituted by C₁₋₆ alkylgroup(s) (preferably, a methyl group),

preferably a C₁₋₆ alkyl group (preferably, a methyl group, an ethylgroup, a propyl group) optionally substituted by 1 to 3 substituentsselected from

(a) a hydroxy group,

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group), and

(c) an amino group optionally mono- or di-substituted by C₁₋₆ alkylgroup(s) (preferably, a methyl group).

R^(8′) is

(1) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl group, apropyl group, an isopropyl group, an isobutyl group, a tert-butyl group,a neopentyl group) optionally substituted by 1 to 3 substituentsselected from

(a) a hydroxy group,

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group, an ethoxy group, apropoxy group, an isopropoxy group) optionally substituted by C₆₋₁₀ arylgroup(s) (preferably, a phenyl group),

(c) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl group, acyclohexyl group) optionally substituted by C₁₋₆ alkoxy group(s)(preferably, a methoxy group),

(d) a C₆₋₁₀ aryl group (preferably, a phenyl group),

(e) a 5- or 6-membered unsaturated heterocyclic group (preferably, animidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionallysubstituted by oxo group(s),

(f) a 5- to 8-membered saturated heterocyclic group (preferably, atetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group,a piperidyl group, an azepanyl group, an azocanyl group, a morpholinylgroup, a 1,1-dioxideisothiazolidinyl group, an oxazolidinyl group, animidazolidinyl group) optionally substituted by 1 to 3 substituentsselected from

-   -   (i) a hydroxy group,    -   (ii) a C₁₋₆ alkyl group (preferably, a methyl group) optionally        substituted by 1 to 3 substituents selected from a hydroxy group        and a C₁₋₆ alkoxy group (preferably, a methoxy group),    -   (iii) a C₁₋₆ alkoxy group (preferably, a methoxy group), and    -   (iv) an oxo group,

(g) a C₃₋₆ cycloalkyloxy group (preferably, a cyclopentyloxy group),

(h) a C₆₋₁₀ aryloxy group (preferably, a phenoxy group),

(i) a 5- or 6-membered unsaturated heterocyclyloxy group (preferably, apyridyloxy group),

(j) a 5- or 6-membered saturated heterocyclyloxy group (preferably, atetrahydrofuryloxy group, a tetrahydropyranyloxy group), and

(k) an amino group optionally mono- or di-substituted by substituentsselected from

-   -   (i) a C₁₋₆ alkyl group (preferably, a methyl group),    -   (ii) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl group, a        propanoyl group, a 2-methylpropanoyl group, a        2,2-dimethylpropanoyl group, a 3-methylbutanoyl group)        optionally substituted by 1 to 3 substituents selected from a        hydroxy group and a C₁₋₆ alkoxy group (preferably, a methoxy        group),    -   (iii) a C₁₋₆ alkoxy-carbonyl group (preferably, a        methoxycarbonyl group, a tert-butoxycarbonyl group) optionally        substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl group),        and    -   (iv) a C₃₋₆ cycloalkyl-carbonyl group (preferably, a        cyclopropylcarbonyl group, a cyclohexylcarbonyl group)        optionally substituted by C₁₋₆ alkoxy group(s) (preferably, a        methoxy group),        (2) a C₁₋₆ alkoxy group (preferably, a methoxy group) optionally        substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl group),        (3) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl group,        cyclohexyl group) optionally substituted by 1 to 3 substituents        selected from

(a) a hydroxy group, and

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group),

(4) a C₆₋₁₀ aryl group (preferably, a phenyl group) optionallysubstituted by C₁₋₆ alkyl group(s) (preferably, a methyl group)optionally substituted by 1 to 3 halogen atoms (preferably, a fluorineatom),

(5) an amino group optionally mono- or di-substituted by C₁₋₆ alkylgroup(s) (preferably, a methyl group) optionally substituted by C₆₋₁₀aryl group(s) (preferably, a phenyl group),

(6) a 5- or 6-membered unsaturated heterocyclic group (preferably, anisoxazolyl group) optionally substituted by C₁₋₆ alkyl group(s)(preferably, a methyl group),(7) a 5- or 6-membered saturated heterocyclic group (preferably, atetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group,a piperidyl group) optionally substituted by 1 to 3 substituentsselected from

(a) a C₁₋₆ alkyl group (preferably, a methyl group),

(b) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl group), and

(c) an oxo group,

(8) a C₃₋₆ cycloalkyloxy group (preferably, a cyclohexyloxy group), or(9) a C₆₋₁₀ aryl-carbonyl group (preferably, a benzoyl group).

Alternatively, R^(7″) and R^(8′) may form, together with the nitrogenatom and carbon atom they are bonded to, a 5- or 6-membered cyclic aminesubstituted by an oxo group (preferably, 2-oxopyrrolidine,2-oxopiperidine, 2-oxooxazolidine) and optionally further substituted by1 to 3 substituents selected from

(a) a hydroxy group,

(b) a C₁₋₆ alkyl group (preferably, a methyl group) optionallysubstituted by hydroxy group(s),

(c) a C₁₋₆ alkoxy group (preferably, a methoxy group), and

(d) a C₃₋₆ cycloalkyl group (preferably, a cyclohexyl group).

As compound [I′], a compound wherein

R^(1′) is

(1) a hydrogen atom,(2) a hydroxy group, or(3) a C₁₋₆ alkoxy group (preferably, a methoxy group, an isopropoxygroup) optionally substituted by C₁₋₁₀ aryl group(s) (preferably, aphenyl group);R^(2′) and R^(3′) are the same or different and each is (1) a hydrogenatom, or(2) a C₁₋₆ alkyl group (preferably, a methyl group) optionallysubstituted by 1 to 3 substituents selected from

(a) a hydroxy group, and

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group);

R^(4′) is

which is bonded to the 5-position or the 6-position of the indole ring,or

which is bonded to the 6-position of the indole ring (preferably,

which is bonded to the 6-position of the indole ring),

-   -   wherein    -   R⁵ is    -   (1) a hydrogen atom, or    -   (2) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl        group), and    -   R⁶ is    -   (1) a hydrogen atom,    -   (2) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl        group, an isopropyl group, an isobutyl group, a tert-butyl        group, a neopentyl group, a 1,2-dimethylpropyl group, a        1,2,2-trimethylpropyl group) optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group, a            propoxy group, an isopropoxy group),        -   (c) a carboxy group,        -   (d) a C₁₋₆ alkoxy-carbonyl group (preferably, a            methoxycarbonyl group, a tert-butoxycarbonyl group),        -   (e) a C₆₋₁₀ aryl group (preferably, a phenyl group),        -   (f) a C₆₋₁₀ aryloxy group (preferably, a phenoxy group),        -   (g) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s) (preferably, a methyl group),        -   (h) a 5- or 6-membered unsaturated heterocyclic group            (preferably, a furyl group, a pyrrolyl group, a thiazolyl            group, a tetrazolyl group, an imidazolyl group) optionally            substituted by C₁₋₆ alkyl group(s) (preferably, a methyl            group), and        -   (i) a 5- or 6-membered saturated heterocyclic group            (preferably, a morpholinyl group),    -   (3) a C₁₋₆ alkoxy group (preferably, a methoxy group),    -   (4) a C₆₋₁₀ aryl group (preferably, a phenyl group), or    -   (5) a 5- or 6-membered unsaturated heterocyclic group        (preferably, a 1,3,4-thiadiazolyl group) optionally substituted        by 1 to 3 substituents selected from        -   (a) a hydroxy group, and        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group), or    -   R^(5′) and R^(6′) form, together with the nitrogen atom they are        bonded to, a 5- or 6-membered cyclic amine (preferably,        pyrrolidine, piperidine, piperazine, morpholine) (said cyclic        amine is optionally condensed with 5- or 6-membered unsaturated        heterocycle (preferably, imidazole)), which is optionally        substituted by 1 to 3 substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl            group),        -   (c) a C₁₋₆ alkoxy group (preferably, a methoxy group), and        -   (d) a C₁₋₆ alkoxy-carbonyl group (preferably, a            tert-butoxycarbonyl group);    -   R^(7″) is    -   (1) a hydrogen atom, or    -   (2) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl        group, a propyl group) optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group), and        -   (c) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s) (preferably, a methyl group)            [preferably,    -   a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl group,        a propyl group) optionally substituted by 1 to 3 substituents        selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group), and        -   (c) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s) (preferably, a methyl group)], and    -   R^(8′) is    -   (1) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl        group, a propyl group, an isopropyl group, an isobutyl group, a        tert-butyl group, a neopentyl group) optionally substituted by 1        to 3 substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group, ethoxy            group, a propoxy group, an isopropoxy group) optionally            substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl            group),        -   (c) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl            group, a cyclohexyl group) optionally substituted by C₁₋₆            alkoxy group(s) (preferably, a methoxy group),        -   (d) a C₆₋₁₀ aryl group (preferably, a phenyl group),        -   (e) a 5- or 6-membered unsaturated heterocyclic group            (preferably, an imidazolyl group, a dihydropyridyl group,            pyrazolyl group) optionally substituted by oxo group(s),        -   (f) a 5- to 8-membered saturated heterocyclic group            (preferably, a tetrahydrofuryl group, a            tetrahydropyranyl-group, a pyrrolidinyl group, a piperidyl            group, an azepanyl group, an azocanyl group, a morpholinyl            group, a 1,1-dioxideisothiazolidinyl group, an oxazolidinyl            group, an imidazolidinyl group) optionally substituted by 1            to 3 substituents selected from            -   (i) a hydroxy group,            -   (ii) a C₁₋₆ alkyl group (preferably, a methyl group)                optionally substituted by 1 to 3 substituents selected                from a hydroxy group and a C₁₋₆ alkoxy group                (preferably, a methoxy group),            -   (iii) a C₁₋₆ alkoxy group (preferably, a methoxy group),                and            -   (iv) an oxo group,        -   (g) a C₃₋₆ cycloalkyloxy group (preferably, a cyclopentyloxy            group),        -   (h) a C₆₋₁₀ aryloxy group (preferably, a phenoxy group),        -   (i) a 5- or 6-membered unsaturated heterocyclyloxy group            (preferably, a pyridyloxy group),        -   (j) a 5- or 6-membered saturated heterocyclyloxy group            (preferably, a tetrahydrofuryloxy group, a            tetrahydropyranyloxy group), and        -   (k) an amino group optionally mono- or di-substituted by            substituents selected from            -   (i) a C₁₋₆ alkyl group (preferably, a methyl group),            -   (ii) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl                group, a propanoyl group, a 2-methylpropanoyl group, a                2,2-dimethylpropanoyl group, a 3-methylbutanoyl group)                optionally substituted by 1 to 3 substituents selected                from a hydroxy group and a C₁₋₆ alkoxy group                (preferably, a methoxy group),            -   (iii) a C₁₋₆ alkoxy-carbonyl group (preferably, a                methoxycarbonyl group, a tert-butoxycarbonyl group)                optionally substituted by C₆₋₁₀ aryl group(s)                (preferably, a phenyl group), and            -   (iv) a C₃₋₆ cycloalkyl-carbonyl group (preferably, a                cyclopropylcarbonyl group, a cyclohexylcarbonyl group)                optionally substituted by C₁₋₆ alkoxy group(s)                (preferably, a methoxy group),    -   (2) a C₁₋₆ alkoxy group (preferably, a methoxy group) optionally        substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl group),    -   (3) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl group, a        cyclohexyl group) optionally substituted by 1 to 3 substituents        selected from        -   (a) a hydroxy group, and        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group),    -   (4) a C₆₋₁₀ aryl group (preferably, a phenyl group) optionally        substituted by C₁₋₆ alkyl group(s) (preferably, a methyl group)        optionally substituted by 1 to 3 halogen atoms (preferably, a        fluorine atom),    -   (5) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (preferably, a methyl group) optionally        substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl group),    -   (6) a 5- or 6-membered unsaturated heterocyclic group        (preferably, an isoxazolyl group) optionally substituted by C₁₋₆        alkyl group(s) (preferably, a methyl group),    -   (7) a 5- or 6-membered saturated heterocyclic group (preferably,        a tetrahydrofuryl group, a tetrahydropyranyl group, a        pyrrolidinyl group, a piperidyl group) optionally substituted by        1 to 3 substituents selected from        -   (a) a C₁₋₆ alkyl group (preferably, a methyl group),        -   (b) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl            group), and        -   (c) an oxo group,    -   (8) a C₃₋₆ cycloalkyloxy group (preferably, a cyclohexyloxy        group), or    -   (9) a C₆₋₁₀ aryl-carbonyl group (preferably, a benzoyl group),        or    -   R^(7′) and R^(8′) form, together with the nitrogen atom and        carbon atom they are bonded to, a 5- or 6-membered cyclic amine        substituted by an oxo group (preferably, 2-oxopyrrolidine,        2-oxopiperidine, 2-oxooxazolidine) and optionally further        substituted by 1 to 3 substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkyl group (preferably, a methyl group)            optionally substituted by hydroxy group(s),        -   (c) a C₁₋₆ alkoxy group (preferably, a methoxy group), and        -   (d) a C₃₋₆ cycloalkyl group (preferably, a cyclohexyl group)            is preferable.

Among the above, a compound wherein

R^(1′) is

(1) a hydrogen atom,(2) a hydroxy group, or(3) a C₁₋₆ alkoxy group (preferably, a methoxy group, an isopropoxygroup) optionally substituted by C₆₋₁₀ aryl group(s) (preferably, aphenyl group);R^(2′) and R^(3′) are the same or different and each is(1) a hydrogen atom, or(2) a C₁₋₆ alkyl group (preferably, a methyl group) optionallysubstituted by 1 to 3 substituents selected from

(a) a hydroxy group, and

(b) a C₁₋₆ alkoxy group (preferably, a methoxy group);

R^(4′) is

which is bonded to the 6-position of the indole ring,

-   -   wherein    -   R^(7″) is a C₁₋₆ alkyl group (preferably, a methyl group, an        ethyl group, a propyl group) optionally substituted by 1 to 3        substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group), and        -   (c) an amino group optionally mono- or di-substituted by            C₁₋₆ alkyl group(s) (preferably, a methyl group), and R^(8′)            is    -   (1) a C₁₋₆ alkyl group (preferably, a methyl group, an ethyl        group, a propyl group, an isopropyl group, an isobutyl group, a        tert-butyl group, a neopentyl group) optionally substituted by 1        to 3 substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group, an            ethoxy group, a propoxy group, an isopropoxy group)            optionally substituted by C₆₋₁₀ aryl group(s) (preferably, a            phenyl group),        -   (c) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl            group, a cyclohexyl group) optionally substituted by C₁₋₆            alkoxy group(s) (preferably, a methoxy group),        -   (d) a C₆₋₁₀ aryl group (preferably, a phenyl group),        -   (e) a 5- or 6-membered unsaturated heterocyclic group            (preferably, imidazolyl group, dihydropyridyl group, a            pyrazolyl group) optionally substituted by oxo group(s),        -   (f) a 5- to 8-membered saturated heterocyclic group            (preferably, a tetrahydrofuryl group, a tetrahydropyranyl            group, a pyrrolidinyl group, a piperidyl group, an azepanyl            group, an azocanyl group, a morpholinyl group, a            1,1-dioxideisothiazolidinyl group, an oxazolidinyl group, an            imidazolidinyl group) optionally substituted by 1 to 3            substituents selected from            -   (i) a hydroxy group,            -   (ii) a C₁₋₆ alkyl group (preferably, a methyl group)                optionally substituted by 1 to 3 substituents selected                from a hydroxy group and a C₁₋₆ alkoxy group                (preferably, a methoxy group),            -   (iii) a C₁₋₆ alkoxy group (preferably, a methoxy group),                and            -   (iv) an oxo group,        -   (g) a C₃₋₆ cycloalkyloxy group (preferably, a cyclopentyloxy            group),        -   (h) a C₆₋₁₀ aryloxy group (preferably, a phenoxy group),        -   (i) a 5- or 6-membered unsaturated heterocyclyloxy group            (preferably, a pyridyloxy group),        -   (j) a 5- or 6-membered saturated heterocyclyloxy group            (preferably, a tetrahydrofuryloxy group, a            tetrahydropyranyloxy group), and        -   (k) an amino group optionally mono- or di-substituted by            substituents selected from            -   (i) a C₁₋₆ alkyl group (preferably, a methyl group),            -   (ii) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl                group, a propanoyl group, a 2-methylpropanoyl group, a                2,2-dimethylpropanoyl group, a 3-methylbutanoyl group)                optionally substituted by 1 to 3 substituents selected                from a hydroxy group and a C₁₋₆ alkoxy group                (preferably, a methoxy group),            -   (iii) a C₁₋₆ alkoxy-carbonyl group (preferably, a                methoxycarbonyl group, a tert-butoxycarbonyl group)                optionally substituted by C₆₋₁₀ aryl group(s)                (preferably, a phenyl group), and            -   (iv) a C₃₋₆ cycloalkyl-carbonyl group (preferably, a                cyclopropylcarbonyl group, a cyclohexylcarbonyl group)                optionally substituted by C₁₋₆ alkoxy group(s)                (preferably, a methoxy group),    -   (2) a C₁₋₆ alkoxy group (preferably, a methoxy group) optionally        substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl group),    -   (3) a C₃₋₆ cycloalkyl group (preferably, a cyclopentyl group, a        cyclohexyl group) optionally substituted by 1 to 3 substituents        selected from        -   (a) a hydroxy group, and        -   (b) a C₁₋₆ alkoxy group (preferably, a methoxy group),    -   (4) a C₆₋₁₀ aryl group (preferably, a phenyl group) optionally        substituted by C₁₋₆ alkyl group(s) (preferably, a methyl group)        optionally substituted by 1 to 3 halogen atoms (preferably, a        fluorine atom),    -   (5) an amino group optionally mono- or di-substituted by C₁₋₆        alkyl group(s) (preferably, a methyl group) optionally        substituted by C₆₋₁₀ aryl group(s) (preferably, a phenyl group),    -   (6) a 5- or 6-membered unsaturated heterocyclic group        (preferably, an isoxazolyl group) optionally substituted by C₁₋₆        alkyl group(s) (preferably, a methyl group),    -   (7) a 5- or 6-membered saturated heterocyclic group (preferably,        a tetrahydrofuryl group, a tetrahydropyranyl group, a        pyrrolidinyl group, a piperidyl group) optionally substituted by        1 to 3 substituents selected from        -   (a) a C₁₋₆ alkyl group (preferably, a methyl group),        -   (b) a C₁₋₆ alkyl-carbonyl group (preferably, an acetyl            group), and        -   (c) an oxo group,    -   (8) a C₃₋₆ cycloalkyloxy group (preferably, a cyclohexyloxy        group), or    -   (9) a C₆₋₁₀ aryl-carbonyl group (preferably, a benzoyl group),        or    -   R^(7′) and R^(8′) form, together with the nitrogen atom and        carbon atom they are bonded to, a 5- or 6-membered cyclic amine        substituted by an oxo group (preferably, 2-oxopyrrolidine,        2-oxopiperidine, 2-oxooxazolidine) and optionally further        substituted by 1 to 3 substituents selected from        -   (a) a hydroxy group,        -   (b) a C₁₋₆ alkyl group (preferably, a methyl group)            optionally substituted by hydroxy group(s),        -   (c) a C₁₋₆ alkoxy group (preferably, a methoxy group), and        -   (d) a C₃₋₆ cycloalkyl group (preferably, a cyclohexyl            group),            that is, a compound represented by the above-mentioned            formula [I′-a] is particularly preferable.

A pharmaceutically acceptable salt of compound [I] may be any salt aslong as it forms a nontoxic salt with the compound of the presentinvention, and examples thereof include salts with inorganic acid, saltswith organic acid, salts with inorganic base, salts with organic base,salts with amino acid and the like.

Examples of the salts with inorganic acid include salts withhydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,hydrobromic acid and the like. Examples of the salts with organic acidinclude salts with oxalic acid, maleic acid, citric acid, fumaric acid,lactic acid, malic acid, succinic acid, tartaric acid, acetic acid,trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonicacid, benzenesulfonic acid, p-toluenesulfonic acid and the like.

Examples of the salts with inorganic base include sodium salt, potassiumsalt, calcium salt, magnesium salt, ammonium salt and the like.

Examples of the salts with organic base include salts with methylamine,diethylamine, trimethylamine, triethylamine, ethanolamine,diethanolamine, triethanolamine, ethylenediamine,tris(hydroxymethyl)methylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, guanidine, pyridine, picoline, choline,cinchonine, meglumine and the like.

Examples of the salts with amino acid include salts with lysine,arginine, aspartic acid, glutamic acid and the like.

When a salt of compound [I] is desired, each salt can be obtained byreacting compound [I] with inorganic base, organic base, inorganic acid,organic acid or amino acid according to a known method.

The “solvate” is compound [I] or a pharmaceutically acceptable saltthereof, which is coordinated with a solvent molecule, and alsoencompasses hydrates. The solvate is preferably a pharmaceuticallyacceptable solvate, examples thereof include a hydrate, ethanolate,dimethyl sulfoxidate and the like of compound [I] or a pharmaceuticallyacceptable salt thereof. Specific examples include semihydrate, 1hydrate, 2 hydrate or 1 ethanolate of compound [I], 1 hydrate of sodiumsalt or 2/3 ethanolate of 2 hydrochloride of compound [I], and the like.

The solvates can be obtained by a known method.

In addition, various “isomers” are present in a compound represented bythe formula [I]. For example, cis form and trans form are present asgeometric isomers, and when an asymmetric carbon atom is present,enantiomers and diastereomers are present as stereoisomers due to theasymmetric carbon atom. Furthermore, when axis asymmetry is present,stereoisomers are present due to the axis asymmetry. Tautomers can alsobe present in some cases.

Alternatively, stereoisomers derived from the direction of an unsharedelectron pair on nitrogen atom may also be present. Therefore, all ofthese isomers and mixtures thereof are encompassed in the scope of thepresent invention. In addition, compound [I] may be labeled with isotope(e.g., ³H, ¹⁴C, ³⁵S etc.).

A deuterium converter obtained by converting ¹H of compound [I] to ²H(D) is also encompassed in a compound represented by the formula [I].

As compound [I] or a pharmaceutically acceptable salt thereof or asolvate thereof, substantially purified compound [I] or apharmaceutically acceptable salt thereof or a solvate thereof ispreferable. More preferred is compound [I] or a pharmaceuticallyacceptable salt thereof or a solvate thereof, which is purified to havea purity of more than 80%.

In the present invention, a prodrug of compound [I] or apharmaceutically acceptable salt thereof, or a solvate thereof(hereinafter to be sometimes abbreviated as the compound of the presentinvention) can also be a useful medicament. The “prodrug” is aderivative of the compound of the present invention having a chemicallyor metabolically degradable group which, after administration to thebody, restores to the original compound by, for example, hydrolysis,solvolysis or decomposition under physiological conditions, and showsinherent efficacy. It includes a noncovalent complex, and a salt.Prodrug is utilized for, for example, improvement of absorption on oraladministration, or targeting to a target moiety. Examples of themodified moiety include, in the compound of the present invention, ahighly reactive functional group such as a hydroxyl group, a carboxylgroup, an amino group and the like.

Specific examples of the hydroxyl-modifying group include an acetylgroup, a propanonyl group, a 2-methylpropanoyl group, a2,2-dimethylpropanoyl group, a palmitoyl group, a benzoyl group, a4-methylbenzoyl group, a dimethylcarbamoyl group, adimethylaminomethylcarbonyl group, a sulfo group, an alanyl group, afumaryl group, a 3-carboxybenzoyl group, a 2-carboxyethylcarbonyl group,a 3-sodium carboxylatobenzoyl group and the like.

Specific examples of the carboxyl-modifying group include a methylgroup, an ethyl group, a propanoyl group, a 2-methylpropanoyl group, abutyl group, an isobutyl group, a tert-butyl group, a2,2-dimethylpropanoyloxymethyl group, a carboxymethyl group, adimethylaminomethyl group, a 1-(acetyloxy)ethyl group, a1-(ethoxycarbonyloxy)ethyl group, a 1-(isopropyloxycarbonyloxy)ethylgroup, a 1-(cyclohexyloxycarbonyloxy)ethyl group, a(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a benzyl group, a phenylgroup, an o-tolyl group, a morpholinoethyl group, anN,N-diethylcarbamoylmethyl group, a phthalidyl group and the like.

Specific examples of the amino-modifying group include a tert-butylgroup, a docosanoyl group, a 2,2-dimethylpropanoylmethyloxy group, analanyl group, a hexylcarbamoyl group, a pentylcarbamoyl group, a3-methylthio-1-(acetylamino)propylcarbonyl group, a1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, a(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, a(5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, atetrahydrofuranyl group, a pyrrolidylmethyl group and the like.

When the indole compound of the present invention is used as amedicament, particularly a pharmaceutical composition, a chemicallystable compound is preferable.

Examples of the “pharmaceutical composition” include oral preparationssuch as tablet, capsule, granule, powder, troche, syrup, emulsion,suspension and the like, and parenteral agents such as externalpreparation, suppository, injection, eye drop, nasal preparations,pulmonary preparation and the like.

The pharmaceutical composition of the present invention is producedaccording to a method known in the art of pharmaceutical preparations,by mixing etc. the compound of the present invention with a suitableamount of at least one kind of pharmaceutically acceptable carrier andthe like as appropriate. While the content of the compound of thepresent invention in the pharmaceutical composition varies depending onthe dosage form, dose and the like, it is, for example, 0.1 to 100 wt %of the whole composition.

Examples of the “pharmaceutically acceptable carrier” include variousorganic or inorganic carrier substances conventionally used aspreparation materials, for example, excipient, disintegrant, binder,glidant, lubricant and the like for solid preparations, and solvent,solubilizing agent, suspending agent, isotonicity agent, bufferingagent, soothing agent and the like for liquid preparations. Wherenecessary, moreover, additives such as preservative, antioxidant,colorant, sweetening agent and the like are used.

Examples of the “excipient” include lactose, sucrose, D-mannitol,D-sorbitol, cornstarch, dextrin, microcrystalline cellulose, crystallinecellulose, carmellose, carmellose calcium, sodium carboxymethyl starch,low-substituted hydroxypropylcellulose, gum arabic and the like.

Examples of the “disintegrant” include carmellose, carmellose calcium,carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium,crospovidone, low-substituted hydroxypropylcellulose,hydroxypropylmethylcellulose, crystalline cellulose and the like.

Examples of the “binder” include hydroxypropylcellulose,hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose,dextrin, starch, gelatin, carmellose sodium, gum arabic and the like.

Examples of the “glidant” include light anhydrous silicic acid,magnesium stearate and the like.

Examples of the “lubricant” include magnesium stearate, calciumstearate, talc and the like.

Examples of the “solvent” include purified water, ethanol, propyleneglycol, macrogol, sesame oil, corn oil, olive oil and the like.

Examples of the “solubilizing agents” include propylene glycol,D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate,sodium citrate and the like.

Examples of the “suspending agent” include benzalkonium chloride,carmellose, hydroxypropylcellulose, propylene glycol, povidone,methylcellulose, glycerol monostearate and the like.

Examples of the “isotonicity agent” include glucose, D-sorbitol, sodiumchloride, D-mannitol and the like.

Examples of the “buffering agent” include sodium hydrogenphosphate,sodium acetate, sodium carbonate, sodium citrate and the like.

Examples of the “soothing agent” include benzyl alcohol and the like.

Examples of the “preservative” include ethyl parahydroxybenzoate,chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid andthe like.

Examples of the “antioxidant” include sodium sulfite, ascorbic acid andthe like.

Examples of the “colorant” include food colors (e.g., Food Color Red No.2 or 3, Food Color Yellow No. 4 or 5 etc.), β-carotene and the like.

Examples of the “sweetening agent” include saccharin sodium, dipotassiumglycyrrhizinate, aspartame and the like.

The pharmaceutical composition of the present invention can beadministered orally or parenterally (e.g., topical, rectal, intravenousadministration etc.) to human as well as mammals other than human (e.g.,mouse, rat, hamster, guinea pig, rabbit, cat, dog, swine, bovine, horse,sheep, monkey etc.). The dose varies depending on the subject ofadministration, disease, symptom, dosage form, administration route andthe like. For example, the daily dose for oral administration to anadult patient (body weight: about 60 kg) is generally within the rangeof about 1 mg to 1 g, based on compound [I] as the active ingredient.This amount can be administered in one to several portions.

The compound of the present invention has an inducible T cell kinase(ITK)-inhibitory activity. Therefore, the compound of the presentinvention can be used as an active ingredient of an agent for thetreatment or prophylaxis of inflammatory diseases, an agent for thetreatment or prophylaxis of allergic diseases, an agent for thetreatment or prophylaxis of autoimmune diseases, an inhibitor ofrejection in transplantation and the like.

To “inhibit ITK” or “has ITK inhibitory activity” means to inhibit thefunction of ITK to eliminate or attenuate the activity or have suchactivity. For example, it means to measure the ITK inhibitory activitybased on the conditions in the below-mentioned Experimental Example 1,and administer a compound having an inhibitory activity to a mammalinclusive of human to inhibit the function of ITK. To “inhibit ITK”preferably means to “inhibit human ITK”. The “ITK inhibitor” ispreferably a “human ITK inhibitor”.

While the inflammatory disease is not particularly limited, examplesthereof include rheumatoid arthritis, inflammatory intestine disease andthe like.

While the allergic disease is not particularly limited, examples thereofinclude atopic dermatitis, asthma, allergic rhinitis and the like.

While the autoimmune disease is not particularly limited, examplesthereof include rheumatoid arthritis, systemic lupus erythematosus,psoriasis, inflammatory intestine disease and the like.

The compound of the present invention can be used in combination withone or a plurality of other medicaments (hereinafter to be also referredto as a concomitant drug) according to a method generally employed inthe medical field (hereinafter to be referred to as combined use).

The administration period of the compound of the present invention and aconcomitant drug is not limited, and they may be administered to anadministration subject as combination preparation, or the bothpreparations may be administered simultaneously or at given intervals asindividual preparations. In addition, the pharmaceutical composition ofthe present invention and a concomitant drug may be used in the form ofa kit. The dose of the concomitant drug is similar to theclinically-employed dose and can be appropriately selected according tothe subject of administration, disease, symptom, dosage form,administration route, administration time, combination and the like. Theadministration form of the concomitant drug is not particularly limited,and it only needs to be combined with the compound of the presentinvention.

Next, one example of the production methods of the compound to practicethe present invention is explained below. However, the production methodof the compound of the present invention is not limited thereto.

Even if no directly corresponding disclosure is found in the followingProduction Methods, the steps may be modified for efficient productionof the compound, such as introduction of a protecting group into afunctional group with deprotection in a subsequent step, subjecting afunctional group as a precursor to each step, followed by conversion toa desired functional group at a suitable stage, changing the order ofProduction Methods and steps, and the like.

The treatment after reaction in each step may be conventional ones,where isolation and purification can be performed as necessary accordingto a method appropriately selected from conventional methods such ascrystallization, recrystallization, distillation, partitioning, silicagel chromatography, preparative HPLC and the like, or a combination ofthose methods.

Production Method 1

wherein R⁹ and R¹⁰ are the same or different and each is anamino-protecting group; and other symbols are as defined above.

Examples of the “amino-protecting group” for R⁹ or R¹⁰ include atert-butoxycarbonyl group, an ethoxycarbonyl group, a trityl group, atetrahydropyranyl group, a methoxymethyl group, a2-(trimethylsilyl)ethoxymethyl group, a p-toluenesulfonyl group and thelike, with preference given to a tert-butoxycarbonyl group.

(Step 1)

Compound [3] can be obtained by subjecting compound [1] and compound [2]to the Suzuki coupling reaction. For example, compound [3] can beobtained by reacting compound [1] with compound [2] in a solvent underheating in the presence of a base and a palladium catalyst. The reactionis preferably performed by gradually adding compound [2] in the presenceof all other reagents under heating.

Examples of the palladium catalyst to be used for the reaction includetetrakistriphenylphosphinepalladium,(bis(diphenylphosphino)ferrocene)palladium dichloride-methylene chloridecomplex and the like.

Examples of the base to be used for the reaction include potassiumphosphate, sodium carbonate, sodium hydrogen carbonate, potassiumcarbonate, triethylamine and the like.

Preferable examples of the solvent to be used for the reaction includeether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether,1,2-dimethoxyethane and the like; alcohol solvents such as methanol,ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents suchas toluene, hexane, xylene and the like; polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like;and a mixed solvent thereof with water.

Compound [1] and compound [2] may be commercially available products, orcan be obtained according to the following production methods 2 and 3,or a conventional method.

(Step 2)

Compound [I] can be obtained by removing R⁹ and R¹⁰ of compound [3] by ageneral deprotection reaction. The deprotection reaction may beperformed under conditions suitable for the kinds or a combination of R⁹and R¹⁰. For example, when both R⁹ and R¹⁰ are tert-butoxycarbonylgroups, compound [I] can be obtained by treating compound [3] in asolvent in the presence of a base at room temperature.

Examples of the base to be used for the reaction include sodiumhydroxide, lithium hydroxide, sodium carbonate and the like.

Preferable examples of the solvent to be used for the reaction includeether solvents such as 1,4-dioxane, tetrahydrofuran and the like;alcohol solvents such as methanol, ethanol, n-propanol, isopropanol andthe like; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, acetonitrile and the like; and a mixed solvent thereof withwater.

Production Method 2

wherein each symbol is as defined above.

(Step 1)

Compound [5] can be obtained by reacting compound [4] with ethyl formatein a solvent in the presence of a base. Examples of the base to be usedfor the reaction include sodium hydride, potassium tert-butoxide, sodiumhydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide,lithium diisopropylamide, lithium hexamethyl disilazide and the like.

Preferable examples of the solvent to be used for the reaction includeether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether,1,2-dimethoxyethane and the like; alcohol solvents such as methanol,ethanol, n-propanol, isopropanol and the like; and polar solvents suchas N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like.

Compound [4] may be a commercially available product, or can be obtainedby a conventional method.

(Step 2)

Compound [6] can be obtained by reacting compound [5] with hydrazine ina solvent at a temperature of from room temperature to under heating.This step is sometimes preferably performed from room temperature tounder heating. In addition, an acid may be used as necessary for thereaction.

Preferable examples of the solvent to be used for the reaction includealcohol solvents such as methanol, ethanol, n-propanol, isopropanol andthe like; and polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, acetonitrile and the like.

Examples of the acid to be used for the reaction include hydrochloricacid, sulfuric acid, p-toluenesulfonic acid, pyridium p-toluenesulfonateand the like.

(Step 3)

Compound [7] can be obtained by reacting compound [6] with iodine in asolvent in the presence of a base at a temperature from room temperatureto under heating.

Examples of the base to be used for the reaction include potassiumhydroxide, sodium hydroxide, potassium carbonate, sodium carbonate andthe like.

Preferable examples of the solvent to be used for the reaction includeether solvents such as 1,4-dioxane, tetrahydrofuran and the like;alcohol solvents such as methanol, ethanol, n-propanol, isopropanol andthe like; polar solvents such as N,N-dimethylformamide, dimethylsulfoxide, acetonitrile and the like; and a mixed solvent thereof withwater.

(Step 4)

Compound [1] can be obtained by introducing an amino-protecting group(R⁹) into compound [7]. For example, when R⁹ is a tert-butoxycarbonylgroup, compound [1] can be obtained by reacting compound [7] withdi-tert-butyl dicarbonate in a solvent from room temperature to underheating in the presence of a base.

Examples of the base to be used for the reaction include tertiary aminessuch as triethylamine, 4-dimethylaminopyridine and the like.

Preferable examples of the solvent to be used for the reaction includeether solvents such as 1,4-dioxane, tetrahydrofuran and the like; estersolvents such as ethyl acetate and the like; hydrocarbon solvents suchas toluene, hexane, xylene and the like; and polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like.

Production Method 3

wherein each symbol is as defined above.

(Step 1)

Compound [9] can be obtained by introducing an amino-protecting group(R¹⁰) into compound [8]. For example, when R¹⁰ is a tert-butoxycarbonylgroup, compound [9] can be obtained by reacting compound [8] withdi-tert-butyl dicarbonate in a solvent from room temperature to underheating in the presence of a base.

Examples of the base to be used for the reaction include tertiary aminessuch as 4-dimethylaminopyridine, triethylamine and the like, withpreference given to 4-dimethylaminopyridine.

Preferable examples of the solvent to be used for the reaction includeether solvents such as 1,4-dioxane, tetrahydrofuran and the like; estersolvents such as ethyl acetate and the like; hydrocarbon solvents suchas toluene, hexane, xylene and the like; and polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like.Compound [8] may be a commercially available product, or can be obtainedby a conventional method.

(Step 2)

Compound [2] can be obtained by reacting compound [9] with borate in asolvent under cooling in the presence of a base. The reaction ispreferably performed by gradually adding dropwise a base under coolingin the presence of borate.

Examples of the borate to be used for the reaction include triisopropylborate, trimethyl borate and the like.

Examples of the base to be used for the reaction include butyllithium,lithium diisopropylamide, lithium hexamethyl disilazide and the like.

Preferable examples of the solvent to be used for the reaction includeether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether,1,2-dimethoxyethane and the like.

Compound [I-b], which is compound [I] wherein R⁴ is a group representedby

which is bonded to the 5-position or the 6-position of the indole ring,can also be produced according to the following production method 4 or7.

Production Method 4

wherein R¹¹ is a carboxy-protecting group; and other symbols are asdefined above.

Examples of the “carboxy-protecting group” for R¹¹ include an alkylgroup such as a methyl group, an ethyl group, a tert-butyl group and thelike, a tert-butyldimethylsilyl group, a benzyl group, amethoxyethoxymethyl group and the like.

(Step 1)

Compound [10] can be obtained in the same manner as in production method1, from compound [1] and compound [2-1]obtained in the same manner as inproduction method 3.

(Step 2)

Compound [11] can be obtained by removing R¹¹ of compound [10] by adeprotection reaction. The deprotection reaction may be performed underconditions suitable for the kind of R¹. For example, when R¹¹ is analkyl group, compound [11] can be obtained by hydrolyzing compound [10]in a solvent in the presence of a base at a temperature from roomtemperature to under heating, and acidifying the obtained solution.

Examples of the base to be used for the reaction include potassiumcarbonate, sodium carbonate, lithium hydroxide, sodium hydroxide,potassium hydroxide, lithium hydride, sodium hydride, potassium hydrideand the like.

Preferable examples of the solvent to be used for the reaction include amixed solvent of water with alcohol solvents such as methanol, ethanol,n-propanol, isopropanol and the like; and a mixed solvent thereof withether solvents such as 1,4-dioxane, tetrahydrofuran and the like.

(Step 3)

Compound [I-b] can be obtained by reacting compound [11] with amine [12]in a solvent in the presence of a condensing agent at a temperature fromcooling to heating. An activator may be used to smoothly perform thereaction.

Examples of the condensing agent to be used for the reaction includeN,N′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide,N,N′-diisopropylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) andthe like.

Examples of the activator to be used for the reaction includehydroxysuccinimide, 1-hydroxybenzotriazole and the like.

Preferable examples of the solvent to be used for the reaction includehydrocarbon solvents such as benzene, toluene, hexane, xylene and thelike; halogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane and the like; ether solvents such as1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and thelike; polar solvents such as N,N-dimethylformamide, dimethyl sulfoxide,acetonitrile and the like; pyridine; and a mixed solvent thereof.

Amine [12] may be a commercially available product, or can be obtainedby a conventional method.

Compound [I-c], which is compound [I] wherein R⁴ is a group representedby

which is bonded to the 5-position or the 6-position of the indole ring,can also be produced by the following production method 5 or 6.

Production Method 5

wherein R¹² is an amino-protecting group; R¹³ is an alkyl group such asa methyl group, an ethyl group, a tert-butyl group and the like, abenzyl group and the like; and other symbols are as defined above.

Examples of the “amino-protecting group” for R¹² include a2-(trimethylsilyl)ethoxymethyl group, a trityl group, atetrahydropyranyl group, a methoxymethyl group, a p-toluenesulfonylgroup and the like, with preference given to a 2-(trimethylsilyl)ethoxymethyl group.

(Step 1)

Compound [13] can be obtained by introducing an amino-protecting group(R¹²) into compound [10]. For example, when R¹² is a2-(trimethylsilyl)ethoxymethyl group, compound [13] can be obtained byreacting compound [10] with 2-(trimethylsilyl)ethoxymethyl chloride in asolvent under cooling in the presence of a base.

Examples of the base to be used for the reaction include sodium hydrideand the like.

Examples of the solvent to be used for the reaction include ethersolvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane,tetrahydrofuran and the like; and polar solvents such asN,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like.

(Step 2)

Compound [14] can be obtained by removing R¹¹ of compound [13]. Thereaction can be performed in the same manner as in step 2 of productionmethod 4.

(Step 3)

Compound [15] can be obtained by subjecting compound [14] to the Curtiusrearrangement with diphenylphosphoryl azide to give the correspondingisocyanate, and reacting the obtained isocyanate with the correspondingalcohol (R¹³OH). The Curtius rearrangement can also be performed byreacting the acid chloride of compound [14] with sodium azide to producethe corresponding acid azide, followed by heating. When the alcohol(R¹³OH) is present in the Curtius rearrangement, isocyanate isimmediately reacted with the alcohol to give compound [15]. For example,when R¹³ is a benzyl group, compound [15] can be obtained by reactingcompound [14] by dropwise addition of diphenylphosphoryl azide in asolvent under heating in the presence of benzyl alcohol and a tertiaryamine.

Examples of the tertiary amine to be used for the reaction includetriethylamine and the like.

Preferable examples of the solvent to be used for the reaction includehydrocarbon solvents such as benzene, toluene, hexane, xylene and thelike; and ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like.

(Step 4)

When R⁷ is not a hydrogen atom, compound [16] can be obtained byintroducing R⁷ by reacting compound [15] with a corresponding alkylatingagent in a solvent under ice-cooling to room temperature in the presenceof a base.

The alkylating agent to be used for the reaction may be any as long asit can introduce R⁷, and examples thereof include methyl iodide, ethyliodide, benzyloxymethane chloride and the like.

Examples of the base to be used for the reaction include sodium hydride,butyllithium, lithium diisopropylamide, lithium hexamethyl disilazideand the like.

Preferable examples of the solvent to be used for the reaction includehydrocarbon solvents such as benzene, toluene, hexane, xylene and thelike; ether solvents such as 1,4-dioxane, diethyl ether,1,2-dimethoxyethane, tetrahydrofuran and the like; and polar solventssuch as N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile and thelike.

When R⁷ is a hydrogen atom, compound [15] can be directly subjected tostep 5 without performing step 4.

(Step 5)

Compound [17] can be obtained by reducing compound [16] by aconventional method. For example, when R¹³ is a benzyl group, compound[17] can be obtained by a conventional method such as catalyticreduction and the like. The catalytic reduction can be performed, forexample, in a solvent in the presence of a metal catalyst from roomtemperature to heating at normal pressure to under pressurization andusing a hydrogen gas. As a hydrogen source, ammonium formate,cyclohexene, dicyclohexene and the like may be used.

Examples of the metal catalyst to be used for the reaction includepalladium carbon, palladium hydroxide, palladium black, Raney-nickel andthe like.

Preferable examples of the solvent to be used for the reaction includealcohol solvents such as methanol, ethanol, n-propanol, isopropanol andthe like; ether solvents such as 1,4-dioxane, tetrahydrofuran and thelike; ester solvents such as ethyl acetate and the like; and a mixedsolvent thereof.

(Step 6)

Compound [19] can be obtained by condensing compound [17] with compound[18] according to an amide condensation method generally used. Forexample, compound [18] is treated with a halogenating agent in a solventat room temperature to give the corresponding acid halide. Then, theobtained acid halide is condensed with compound [17] in the presence ofa tertiary amine or pyridine from cooling to room temperature to givecompound [19].

Examples of the halogenating agent to be used for the reaction includeoxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphoruspentachloride and the like.

Examples of the tertiary amine to be used for the reaction includetriethylamine and the like.

Preferable examples of the solvent to be used for the reaction includehalogenated solvents such as dichloromethane, chloroform, carbontetrachloride, 1,2-dichloroethane and the like; ether solvents such as1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and thelike; and a mixed solvent thereof with water.

Compound [18] may be a commercially available product, or can beobtained according to a conventional method. When the corresponding acidhalide is commercially available, it may also be used.

In addition, compound [19] can also be obtained by condensing compound[17] and compound [18] in the same manner as in step 3 of productionmethod 4.

(Step 7)

Compound [I-c] can be obtained by removing R¹² of compound [19] by adeprotection reaction. The deprotection reaction may be performed usingconditions suitable for the kind of R¹². For example, when R¹² is a2-(trimethylsilyl)ethoxymethyl group, compound [I-c] can be obtained byreacting compound [19] in a solvent under heating in the presence oftetrabutylammonium fluoride and ethylenediamine.

Preferable examples of the solvent to be used for the reaction includeether solvents such as 1,4-dioxane, tetrahydrofuran and the like; andpolar solvents such as N,N-dimethylformamide, dimethyl sulfoxide,acetonitrile and the like.

Production Method 6

wherein each symbol is as defined above.

(Step 1)

Compound [20] can be obtained by removing R¹² of compound [16] obtainedin step 4 of production method 5. The reaction can be performed in thesame manner as in step 7 of production method 5.

(Step 2)

Compound [21] can be obtained by subjecting compound [20] to a reductionreaction. The reaction can be performed in the same manner as in step 5of production method 5.

(Step 3)

Compound [22] can be obtained by condensing compound [21] and compound[18]. The reaction can be performed in the same manner as in step 6 ofproduction method 5. Alternatively, compound [I-c] is sometimes directlyobtained by the above-mentioned reaction without performing step 4.

(Step 4)

Compound [I-c] can be obtained from compound [22] by removing an acylgroup on the pyrazole ring. For example, compound [I-c] can be obtainedby hydrolyzing compound [22] in a solvent from room temperature toheating in the presence of a base.

Examples of the base to be used for the reaction include potassiumcarbonate, sodium carbonate, lithium hydroxide, sodium hydroxide,potassium hydroxide, lithium hydride, sodium hydride, potassium hydrideand the like.

Examples of the solvent to be used for the reaction include aqueousalcohol solvents such as methanol, ethanol, n-propanol, isopropanol andthe like; and a mixed solvent thereof with ether solvents such as1,4-dioxane, tetrahydrofuran and the like.

Production Method 7

(Step 1)

Compound [24] can be obtained by condensing compound [14] obtained instep 2 of production method 5 with amine [23]. The reaction can beperformed in the same manner as in step 3 of production method 4.

(Step 2)

Compound [25] can be obtained by reacting compound [23] with thecorresponding alkylating agent to introduce R⁵. The reaction can beperformed in the same manner as in step 4 of production method 5.

(Step 3)

Compound [I-b] can be obtained by removing R¹² of compound [25] by adeprotection reaction. The reaction can be performed in the same manneras in step 7 of production method 5.

EXAMPLES

The present invention is explained in detail in the following byreferring to Reference Examples, Examples and Experimental Example,which are not to be construed as limitative.

The room temperature in Reference Examples and Examples means 1-40° C.

Reference Example 1 Production of tert-butyl3-iodo-6,6-dimethyl-4,5,6,7-tetrahydroindazole-1-carboxylate (Step 1)Production of 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole

Under a nitrogen atmosphere, to a suspension of sodium hydride (28 g,697 mmol) in tetrahydrofuran (500 ml) was added dropwise a solution of3,3-dimethylcyclohexanone (80 g, 634 mmol) in tetrahydrofuran (250 ml)under ice-cooling over about 1 hr, and the mixture was stirred for 1 hr.Then, a solution of ethyl formate (99 g, 1.3 mol) in tetrahydrofuran(250 ml) was added dropwise over about 1 hr, and the mixture was stirredunder ice-cooling for 1 hr, and at room temperature for 1 hr. To thereaction mixture were added water and ethyl acetate, and the organiclayer was separated and extracted with 2 N aqueous sodium hydroxidesolution. The aqueous layer was acidified with concentrated hydrochloricacid, and extracted with ethyl acetate. Then, the organic layer waswashed with saturated brine, and dried over sodium sulfate. Sodiumsulfate was removed by filtration, and the filtrate was concentratedunder reduced pressure to give4,4-dimethyl-2-oxocyclohexanecarbaldehyde. To a solution of the obtained4,4-dimethyl-2-oxocyclohexanecarbaldehyde in methanol (376 ml) was addeddropwise a solution of hydrazine monohydrate (31 ml, 640 mmol) inmethanol (31 ml) with heating under reflux over about 1 hr, and themixture was stirred for 15 min. The reaction mixture was concentratedunder reduced pressure, ethyl acetate and water were added, and theorganic layer was separated. Then, the organic layer was washed withsaturated brine, and dried over sodium sulfate. Sodium sulfate wasremoved by filtration, and the filtrate was concentrated under reducedpressure to give 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole. To asolution of the obtained 6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole inN,N-dimethylformamide (1.4 L) were added iodine (232 g, 915 mmol) andpotassium hydroxide (121 g, 1.8 mol) at room temperature, and themixture was stirred for about 4 hr. Then, under ice-cooling, an aqueoussolution (800 ml) of sodium hydrogensulfite (80 g) was added dropwise.Water (2 L) was added, and the mixture was extracted with ethyl acetate.The organic layer was washed successively with water and saturatedbrine, and dried over sodium sulfate. Sodium sulfate was removed byfiltration, and the filtrate was concentrated under reduced pressure.Then, hexane (350 ml) was added to the residue, and the mixture wasstirred at room temperature. The precipitated crystals were collected byfiltration, washed with hexane, and dried under reduced pressure to give3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (41 g, yield 23%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.94 (s, 6H), 1.47 (t, 2H, J=6.38 Hz), 2.21(t, 2H, J=6.38 Hz), 2.33 (s, 2H), 12.69 (s, 1H).

(Step 2) Production of tert-butyl3-iodo-6,6-dimethyl-4,5,6,7-tetrahydroindazole-1-carboxylate

To a solution of 3-iodo-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole (41g, 147 mmol), triethylamine (22 ml, 155 mmol) and4-dimethylaminopyridine (824 mg, 7 mmol) in tetrahydrofuran (163 ml) wasadded dropwise a solution of di-tert-butyl dicarbonate (34 g, 155 mmol)in tetrahydrofuran (41 ml) at room temperature over 40 min, and themixture was stirred for 30 min. Then, the reaction mixture wasconcentrated under reduced pressure. The residue was slurry-washed inhexane (130 ml) at 60° C. and ice-cooled. The crystals were collected byfiltration, washed with hexane, and dried under reduced pressure to givethe title compound (53 g, yield 95%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.95 (s, 6H), 1.46 (t, 2H, J=6.38 Hz), 1.56(s, 9H), 2.23 (t, 2H, J=6.26 Hz), 2.63 (s, 2H).

Reference Example 2 Production of 1-tert-butyl 6-methyl2-boronylindole-1,6-dicarboxylate (Step 1) Production of methyl1H-indole-6-carboxylate

Under a nitrogen atmosphere, to a solution of 1H-indole-6-carboxylicacid (121 g, 752 mmol) in N,N-dimethylformamide (360 ml) was addedpotassium carbonate (124 g, 900 mmol), and the mixture was stirred atroom temperature for 1 hr. Then, iodomethane (56 ml, 900 mmol) was addeddropwise at room temperature over 15 min, and the mixture was stirredfor 2 hr. Then, to the reaction solution were added water (1.2 L) andhexane (100 ml), and the mixture was stirred at room temperature for 1hr. The precipitated crystals were collected by filtration, washedsuccessively with water and hexane, and dried under reduced pressure togive the title compound (115 g, yield 87%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 3.85 (3H, s), 6.53 (1H, d, J=1.61 Hz),7.60-7.63 (3H, m), 8.07 (1H, s), 11.48 (1H, s).

(Step 2) Production of 1-tert-butyl 6-methyl indole-1,6-dicarboxylate

To a solution of methyl 1H-indole-6-carboxylate (124 g, 708 mmol) intetrahydrofuran (500 ml) was added 4-dimethylaminopyridine (865 mg, 7mmol). Then, a solution of di-tert-butyl dicarbonate (156 g, 715 mmol)in tetrahydrofuran (150 ml) was added dropwise at room temperature overabout 1 hr, and the mixture was stirred for 1 hr. The reaction mixturewas concentrated, and the residue was purified by silica gelchromatography to give the title compound (193 g, yield 99%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.65 (9H, s), 3.89 (3H, s), 6.82 (1H, dd,J=3.63, 0.86 Hz), 7.74 (1H, d, J=8.06 Hz), 7.85 (1H, dd, J=8.06, 0.86Hz), 7.87 (1H, d, J=3.63 Hz), 8.76 (1H, d, J=0.81 Hz).

(Step 3) Production of 1-tert-butyl 6-methyl2-boronylindole-1,6-dicarboxylate

To a solution of 1-tert-butyl 6-methyl indole-1,6-dicarboxylate (107 g,389 mmol) in tetrahydrofuran (135 ml) was added triisopropyl borate (135ml, 584 mmol), and the inside temperature was cooled to −5° C. Then, asolution (253 ml, 506 mmol) of lithium diisopropylamide in hexane wasadded dropwise over 1.5 hr while maintaining the inside temperature at−5° C. or below, and the mixture was further stirred for 1 hr. Then, tothe reaction solution was added dropwise 10% aqueous citric acidsolution (1.2 L) under ice-cooling. The aqueous layer was extractedthree times with ethyl acetate. The combined organic layers were washedwith saturated brine, and dried over magnesium sulfate. Magnesiumsulfate was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was slurry-washed with a mixedsolvent of ethyl acetate (333 ml) and hexane (666 ml), and theprecipitate was collected by filtration, washed with hexane, and driedunder reduced pressure to give the title compound (73 g, yield 59%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.62 (s, 9H), 3.88 (s, 3H), 6.72 (d, 1H,J=0.88 Hz), 7.68 (t, 1H, J=4.08 Hz), 7.82 (dd, 1H, J=8.16, 1.54 Hz),8.33 (s, 2H), 8.78 (t, 1H, J=0.77 Hz).

Reference Example 3 Production of (S)-2-(morpholin-4-yl)propionic acid(Step 1) Production of benzyl (S)-2-(morpholin-4-yl)propionate

Under an argon atmosphere, to a solution of L-alanine benzyl estertosylate (3.4 g, 9.7 mmol) and triethylamine (6.8 ml) in dimethylsulfoxide (17 ml) was added a solution of1-bromo-2-(2-bromoethoxy)ethane (1.5 ml, 12 mmol) in dimethyl sulfoxide(3 ml) under ice-cooling, and the mixture was stirred at roomtemperature for 24 hr. To the reaction solution were added water andethyl acetate, and the organic layer was separated. Then, the organiclayer was washed with saturated brine, and dried over sodium sulfate.Sodium sulfate was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give the title compound (1.6 g, yield 64%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.20 (d, 3H, J=7.25 Hz), 2.44-2.59 (m, 4H),3.35 (q, 1H, J=7.25 Hz), 3.47-3.59 (m, 4H), 5.16-5.09 (m, 2H), 7.29-7.40(m, 5H).

(Step 2) Production of (S)-2-(morpholin-4-yl)propionic acid

Under an argon atmosphere, to a solution of benzyl(S)-2-(morpholin-4-yl)propionate (43 g, 172 mmol) in methanol (430 ml)was added 20% palladium hydroxide-carbon (4.3 g) at room temperature,and the mixture was stirred for 3 hr under a hydrogen atmosphere atnormal pressure. The reaction mixture was filtered through celite, andthe filtrate was concentrated under reduced pressure to give the titlecompound (25.4 g, 93%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.17 (d, 3H, J=6.98 Hz), 2.47-2.63 (m, 4H),3.17 (q, 1H, J=6.98 Hz), 3.50-3.63 (m, 4H).

Reference Example 4 Production of (3-oxomorpholin-4-yl)acetic acid(Step 1) Production of 2-chloro-N-(2-hydroxyethyl)acetamide

Under an argon atmosphere, to a solution of 2-aminoethanol (5 g, 82mmol) and triethylamine (11.4 ml, 82 mmol) in tetrahydrofuran (60 ml)was added dropwise chloroacetyl chloride (6.2 ml, 78 mmol) underice-cooling over 30 min, and the mixture was stirred for 1 hr. Thereaction mixture was further stirred at room temperature for 3 hr, anddried over magnesium sulfate. Magnesium sulfate was removed byfiltration, and the filtrate was concentrated under reduced pressure.The residue was purified by silica gel chromatography to give the titlecompound (3.2 g, yield 30%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 3.16 (q, 2H, J=5.87 Hz), 3.42 (q, 2H,J=5.87 Hz), 4.06 (s, 2H), 4.71 (t, 1H, J=5.45 Hz), 8.18 (s, 1H).

(Step 2) Production of morpholin-3-one

Under an argon atmosphere, to a solution of2-chloro-N-(2-hydroxyethyl)acetamide (3.2 g, 23 mmol) in tetrahydrofuran(64 ml) was added sodium hydride (1.2 g, 30 mmol) under ice-cooling, andthe mixture was stirred for 1 hr. Then, the mixture was stirred at roomtemperature for 1 hr, and further at 60° C. for 4 hr. After cooling,water (540 μl) was added, and the reaction mixture was dried overmagnesium sulfate. Magnesium sulfate was removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography to give the title compound (232mg, yield 10%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 3.20-3.23 (m, 2H), 3.70-3.73 (m, 2H), 3.96(s, 2H), 7.88-8.07 (brs, 1H).

(Step 3) Production of benzyl (3-oxomorpholin-4-yl)acetate

Under an argon atmosphere, to a solution of morpholin-3-one (220 mg, 2.2mmol) in N,N-dimethylformamide (2.2 ml) was added sodium hydride (105mg, 2.6 mmol) under ice-cooling, and the mixture was stirred for 1 hr.Then, benzyl bromoacetate (379 μl, 2.4 mmol) was added, and the mixturewas stirred for 2 hr. To the reaction solution were added water andethyl acetate, and the organic layer was separated. The aqueous layerwas extracted twice with ethyl acetate, and the combined organic layerswere washed successively with water and saturated brine, and dried oversodium sulfate. Sodium sulfate was removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography to give the title compound (321mg, yield 59%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 3.40-3.43 (m, 2H), 3.83-3.85 (m, 2H), 4.08(s, 2H), 4.21 (s, 2H), 5.16 (s, 2H), 7.32-7.41 (m, 5H).

(Step 4) Production of (3-oxomorpholin-4-yl)acetic acid

Under an argon atmosphere, to a solution of benzyl(3-oxomorpholin-4-yl)acetate (319 mg, 1.3 mmol) in methanol (5 ml) wasadded 20% palladium hydroxide-carbon (64 mg) at room temperature. Then,the mixture was stirred for 2 hr under a hydrogen atmosphere at normalpressure. The reaction mixture was filtered through celite, and thefiltrate was concentrated under reduced pressure to give the titlecompound (206 mg, yield over weight).

¹H-NMR (400 MHz, DMSO-d₆) δ: 3.37-3.40 (m, 2H), 3.82-3.84 (m, 2H), 4.03(s, 2H), 4.06 (s, 2H), 12.22-13.57 (brs, 1H).

Reference Example 5 Production of tert-butyl6-benzyloxymethyl-3-iodo-6-methyl-4,5,6,7-tetrahydroindazole-1-carboxylate(Step 1) Production of 7-methyl-1,4-dioxaspiro[4.5]decan-8-one

Under a nitrogen atmosphere, to a solution of lithiumbis(trimethylsilyl)amide (1M, 100 ml, 100 mmol) in tetrahydrofuran (200ml) was added dropwise a solution of 1,4-dioxaspiro[4.5]decan-8-one(15.6 g, 100 mmol) in tetrahydrofuran (50 ml) at −78° C. over about 30min, and the mixture was stirred for 30 min. Then, methyl iodide (2.5ml, 120 mmol) was added dropwise over 5 min, and the mixture was stirredat −78° C. for 30 min, and at room temperature for 2 hr. To the reactionmixture was added saturated aqueous ammonium chloride solution, and themixture was extracted three times with diethyl ether. The combinedorganic layers were dried over magnesium sulfate. Magnesium sulfate wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography to givethe title compound (10.6 g, yield 62%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.90 (3H, d, J=6.62 Hz), 1.65 (1H, t,J=13.01 Hz), 1.84-2.04 (3H, m), 2.19 (1H, ddd, J=14.50, 5.13, 3.03 Hz),2.49-2.69 (2H, m), 3.85-4.06 (4H, m).

(Step 2) Production of7-hydroxymethyl-7-methyl-1,4-dioxaspiro[4.5]decan-8-one

7-Methyl-1,4-dioxaspiro[4.5]decan-8-one (10.5 g, 62 mmol) was dissolvedin methanolic potassium hydroxide solution (10 w/w %, 60 g). To thesolution was added dropwise a solution of aqueous formaldehyde solution(37%, 4.6 ml) in methanol (5 ml) under ice-cooling over 20 min, and themixture was stirred for 30 min. Then, to the reaction mixture were added1 N hydrochloric acid and saturated aqueous ammonium chloride solution,and the mixture was extracted three times with chloroform. The combinedorganic layers were dried over magnesium sulfate. Magnesium sulfate wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography to givethe title compound (6.9 g, yield 56%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.98 (3H, s), 1.67 (1H, dd, J=14.00, 1.41Hz), 1.86-1.97 (2H, m), 2.08 (1H, dd, J=14.00, 1.61 Hz), 2.33-2.48 (2H,m), 3.42-3.50 (2H, m), 3.90-3.95 (4H, m), 4.63 (1H, t, J=5.24 Hz).

(Step 3) Production of (7-methyl-1,4-dioxaspiro[4.5]deca-7-yl)methanol

To a solution of 7-hydroxymethyl-7-methyl-1,4-dioxaspiro[4.5]decan-8-one(6.9 g, 65 mmol) in methanol (40 ml) was addedp-toluenesulfonylhydrazide (7.4 g, 40 mmol), and the mixture was heatedunder reflux for 3 hr. Then, to the reaction solution were addedmethanol (120 ml), sodium cyanoborohydride (2.9 g, 46 mmol) and asolution (100 ml) of zinc chloride (3.1 g, 23 mmol) in methanol, and themixture was heated under reflux for 2 hr. After cooling, 1 N aqueoussodium hydroxide solution (700 ml) was added, the mixture was filteredthrough celite, and the filtrate was extracted three times with ethylacetate. The combined organic layers were washed successively with waterand saturated brine, and dried is over sodium sulfate. Sodium sulfatewas removed by filtration, and the filtrate was concentrated underreduced pressure. The residue was purified by silica gel chromatographyto give the title compound (4.0 g, yield 61%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.96 (3H, s), 1.18-1.87 (8H, m), 3.18 (1H,d, J=8.06 Hz), 3.35 (1H, dd, J=10.88, 6.45 Hz), 3.51 (1H, dd, J=10.88,9.07 Hz), 3.93-3.94 (4H, m).

(Step 4) Production of7-benzyloxymethyl-7-methyl-1,4-dioxaspiro[4.5]decane

Under a nitrogen atmosphere, to a solution of(7-methyl-1,4-dioxaspiro[4.5]deca-7-yl)methanol (4.0 g, 21 mmol) inN,N-dimethylformamide (40 ml) was added sodium hydride (1.1 g, 27 mmol)under ice-cooling, and the mixture was stirred for 30 min. Then, to thereaction mixture was added benzyl bromide (3.1 ml, 25 mmol) at roomtemperature, and the mixture was further stirred for 1 hr. To thereaction mixture were added diethyl ether and water, and the organiclayer was separated. Then, the organic layer was washed successivelywith water and saturated brine, and dried over sodium sulfate. Sodiumsulfate was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography to give the title compound (5.7 g, yield 93%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.95 (3H, s), 1.14-1.19 (1H, m), 1.32-1.59(7H, m), 3.20 (2H, dd, J=28.41, 8.66 Hz), 3.77-3.85 (4H, m), 4.45 (2H,s), 7.29-7.33 (5H, m).

(Step 5) Production of 3-benzyloxymethyl-3-methylcyclohexanone

To a solution of 7-benzyloxymethyl-7-methyl-1,4-dioxaspiro[4.5]decane(5.3 g, 19 mmol) in a mixed solvent of acetone (42 ml) and water (11 ml)was added pyridinium p-toluenesulfonate (4.8 g, 19 mmol), and themixture was stirred with heating at 80° C. for 2 hr. After cooling, tothe reaction mixture were added ethyl acetate and water, and the organiclayer was separated. The aqueous layer was extracted with ethyl acetate,and the combined organic layers were washed successively with water andsaturated brine, and dried over sodium sulfate. Sodium sulfate wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography to givethe title compound (3.9 g, yield 88%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 0.88 (3H, s), 1.43-1.49 (1H, m), 1.72-1.84(3H, m), 2.01 (1H, dt, J=13.67, 1.43 Hz), 2.17-2.26 (2H, m), 2.32 (1H,d, J=13.45 Hz), 3.17 (2H, dd, J=10.81, 8.82 Hz), 4.47 (2H, s), 7.26-7.38(5H, m).

(Step 6) Production of tert-butyl6-benzyloxymethyl-3-iodo-6-methyl-4,5,6,7-tetrahydroindazole-1-carboxylate

In the same manner as in Reference Example 1, the title compound (3.8 g)was obtained from 3-benzyloxymethyl-3-methylcyclohexanone (3.9 g).

Reference Example 6 Production of (2-oxopiperidin-1-yl)acetic acid(Step 1) Production of benzyl (2-oxopiperidin-1-yl)acetate

Under a nitrogen atmosphere, to a solution of piperidin-2-one (9.8 g, 99mmol) in N,N-dimethylformamide (100 ml) was added sodium hydride (4.4 g,110 mmol) under ice-cooling, and the mixture was stirred for 1 hr. Then,benzyl bromoacetate (19 ml, 120 mmol) was added, and the mixture wasfurther stirred for 2 hr. To the reaction mixture were added ethylacetate and water, and the organic layer was separated, washedsuccessively with water and saturated brine, and dried over sodiumsulfate. Sodium sulfate was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give the title compound (6.0 g, yield 24%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.62-1.66 (4H, m), 2.11 (2H, t, J=6.45 Hz),3.10-3.12 (2H, m), 4.21 (2H, s), 5.18 (2H, s), 7.21-7.40 (5H, m).

(Step 2) Production of (2-oxopiperidin-1-yl)acetic acid

Under a nitrogen atmosphere, to a solution of benzyl(2-oxopiperidin-1-yl)acetate (6.0 g, 24 mmol) in methanol (60 ml) wasadded 20% palladium hydroxide-carbon (400 mg) at room temperature, andthe mixture was stirred for 4 hr under a hydrogen atmosphere at normalpressure. The reaction mixture was filtered through celite, and thefiltrate was concentrated under reduced pressure to give the titlecompound (4.0 g, yield over weight).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.71-1.74 (4H, m), 2.23 (2H, t, J=6.04 Hz),3.17-3.31 (2H, m), 3.94 (2H, s), 12.58 (1H, s).

Example 1 Production ofN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methylacetamide(Step 1) Production of 1-tert-butyl 6-methyl 2-(l-tert-butoxycarbonyl-s6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)indole-1,6-dicarboxylate

Under an argon atmosphere, to a solution of tert-butyl3-iodo-6,6-dimethyl-4,5,6,7-tetrahydroindazole-1-carboxylate obtained inReference Example 1 (49 g, 130 mmol), potassium phosphate (110 g, 520mmol) and (bis(diphenylphosphino)ferrocene)palladiumdichloride-methylene chloride complex (11 g, 13 mmol) in a mixed solventof 1,4-dioxane (780 ml) and water (330 ml) was added 1-tert-butyl6-methyl 2-boronylindole-1,6-dicarboxylate (42 g, 130 mmol) obtained inReference Example 2 in portions of 2 g with heating at 110° C. over 15min, and the mixture was stirred for 5 min. After cooling, to thereaction mixture were added water and ethyl acetate, and the organiclayer was separated. Then, the organic layer was washed successivelywith water and saturated brine, and dried over sodium sulfate. Sodiumsulfate was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography to give the title compound (40 g, yield 58%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.01 (s, 6H), 1.40 (s, 9H), 1.48 (t, 2H,J=6.15 Hz), 1.57 (s, 9H), 2.41 (t, 2H, J=5.80 Hz), 2.72 (s, 2H), 3.90(s, 3H), 7.06 (s, 1H), 7.77 (d, 1H, J=8.35 Hz), 7.89 (dd, 1H, J=8.35,1.16 Hz), 8.73 (t, 1H, J=0.70 Hz).

(Step 2) Production of methyl2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl) indole-6-carboxylate

To a solution of 1-tert-butyl 6-methyl2-(1-tert-butoxycarbonyl-6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)indole-1,6-dicarboxylate(39 g, 75 mmol) in a mixed solvent of methanol (180 ml) andtetrahydrofuran (120 ml) was added dropwise 2 N aqueous sodium hydroxidesolution (149 ml, 298 mmol) under ice-cooling over 15 min, and themixture was stirred for 15 min. Then, 1 N hydrochloric acid was addeddropwise to adjust the pH to 5. The precipitated crystals were collectedby filtration, washed with water, and dried under reduced pressure togive the title compound (23 g, yield 97%).

¹H-NMR (400 MHz, DMSO-d₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J=6.38 Hz), 2.42(s, 2H), 2.68 (t, 2H, J=6.15 Hz), 3.85 (s, 3H), 6.67 (s, 1H), 7.59 (s,2H), 8.07 (s, 1H), 11.71 (s, 1H), 12.66 (s, 1H).

(Step 3) Production of methyl2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-H-indole-6-carboxylate

Under an argon atmosphere, to a solution of methyl2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)indole-6-carboxylate(23 g, 71 mmol) in N,N-dimethylformamide (230 ml) was added sodiumhydride (6.3 g, 157 mmol) in portions of about 500 mg at an insidetemperature of −10° C., and the mixture was stirred for 30 min. Then,2-(trimethylsilyl)ethoxymethyl chloride (26 g, 157 mmol) was addeddropwise over 15 min, and the mixture was further stirred for 2 hr. Tothe reaction mixture were added ethyl acetate and water, and the organiclayer was separated. Then, the organic layer was washed successivelywith water and saturated brine, and dried over sodium sulfate. Sodiumsulfate was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography to give the title compound (33 g, yield 80%). ¹H-NMR (400MHz, DMSO-d₆) δ: −0.21 (s, 9H), −0.03 (s, 9H), 0.68 (t, 2H, J=8.00 Hz),0.87 (t, 2H, J=8.12 Hz), 1.03 (s, 6H), 1.54 (t, 2H, J=6.26 Hz), 2.50 (s,2H), 2.63 (t, 2H, J=6.26 Hz), 3.30-3.31 (m, 2H), 3.59 (t, 2H, J=8.00Hz), 3.87 (s, 3H), 5.42 (s, 2H), 6.14 (s, 2H), 6.83 (d, 1H, J=0.70 Hz),7.67-7.72 (m, 2H), 8.22 (s, 1H).

(Step 4) Production of2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-H-indole-6-carboxylicacid

To a solution of methyl2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylate (33 g, 57 mmol) in a mixed solventof tetrahydrofuran (165 ml) and methanol (165 ml) was added 4 N aqueoussodium hydroxide solution (71 ml, 284 mmol), and the mixture was heatedat 60° C. for 2 hr. After cooling, the reaction mixture wasconcentrated, 10% aqueous citric acid solution was added to the residueto adjust the pH to 5, and the mixture was extracted with ethyl acetate.Then, the organic layer was washed with saturated brine, and dried oversodium sulfate. Sodium sulfate was removed by filtration, and thefiltrate was concentrated under reduced pressure to give the titlecompound (31 g, yield 97%). ¹H-NMR (400 MHz, DMSO-d₆) δ: −0.21-−0.20 (m,9H), −0.05-−0.03 (m, 9H), 0.68-0.71 (m, 2H), 0.85-0.91 (m, 2H), 1.03 (s,6H), 1.54 (t, 2H, J=6.06 Hz), 2.63 (t, 2H, J=5.95 Hz), 3.57-3.61 (m,2H), 5.42 (s, 2H), 6.13 (d, 2H, J=3.53 Hz), 6.82 (t, 1H, J=3.42 Hz),7.65-7.70 (m, 2H), 8.20 (s, 1H).

(Step 5) Production of benzyl(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-H-indol-6-yl)carbamate

Under an argon atmosphere, to a solution of2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylicacid (26 g, 45 mmol), triethylamine (8.2 ml, 59 mmol) and benzyl alcohol(18 ml, 180 mmol) in toluene (260 ml) was added dropwisediphenylphosphoryl azide (12 ml, 54 mmol) at 115° C. over 2 hr. Aftercooling, water was added to the reaction mixture, and the organic layerwas separated. Then, the organic layer was washed successively withwater and saturated brine, and dried over magnesium sulfate. Magnesiumsulfate was removed by filtration, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gelchromatography, and slurry-washed in hexane (210 ml) with heating at 60°C. The resulting crystals were collected by filtration, washed withhexane, and dried under reduced pressure to give the title compound (28g, yield 91%). ¹H-NMR (400 MHz, DMSO-d₆) δ: −0.19 (s, 9H), −0.03 (s,9H), 0.69 (t, 2H, J=8.16 Hz), 0.86 (t, 2H, J=8.05 Hz), 1.02 (s, 6H),1.52 (t, 2H, J=6.18 Hz), 2.59 (t, 2H, J=6.06 Hz), 3.58 (t, 2H, J=8.05Hz), 5.17 (s, 2H), 5.38 (s, 2H), 5.96 (s, 2H), 6.61 (s, 1H), 7.10 (dd,1H, J=8.49, 1.65 Hz), 7.34-7.46 (m, 6H), 7.86 (s, 1H), 9.71 (s, 1H).

(Step 6) Production of benzylN-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylcarbamate

Under an argon atmosphere, to a solution of benzyl(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)carbamate (3 g, 4.6 mmol) in N,N-dimethylformamide (30 ml) was addedsodium hydride (219 mg, 5.5 mmol) under ice-cooling, and the mixture wasstirred for 10 min. Then, to the reaction mixture was added methyliodide (0.6 ml, 6.9 mmol), and the mixture was further stirred for 3 hr.To the reaction mixture were added ethyl acetate and water, and theorganic layer was separated. Then, the organic layer was washedsuccessively with water and saturated brine, and dried over sodiumsulfate. Sodium sulfate was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give the title compound (2.2 g, yield 69%). ¹H-NMR(400 MHz, DMSO-d₆) δ: −0.21 (s, 9H), −0.03 (s, 9H), 0.66 (t, 2H, J=8.01Hz), 0.86 (t, 2H, J=8.01 Hz), 1.02 (s, 6H), 1.53 (t, 2H, J=6.01 Hz),2.49 (s, 2H), 2.60 (t, 2H, J=6.01 Hz), 3.29 (s, 3H), 3.29 (t, 2H,J=8.01), 3.59 (t, 2H, J=8.01 Hz), 5.09 (s, 2H), 5.39 (s, 2H), 6.00 (s,2H), 6.70 (s, ¹H), 7.03 (dd, 1H, J=8.41, 2.00 Hz), 7.26-7.37 (m, 5H),7.44-7.59 (m, 2H).

(Step 7) Production ofN-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylamine

A solution of benzylN-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylcarbamate(2.2 g, 3.1 mmol), 10% palladium-carbon (216 mg) and ammonium formate(989 mg, 16 mmol) in ethanol (30 ml) was heated under reflux for 2.5 hr.After cooling, the reaction mixture was filtered through celite, and thefiltrate was concentrated. The residue was purified by silica gelchromatography to give the title compound (1.4 g, yield 79%). ¹H-NMR(400 MHz, DMSO-d₆) δ: −0.18 (s, 9H), −0.03 (s, 9H), 0.69 (t, 2H, J=8.41Hz), 0.86 (t, 2H, J=8.41 Hz), 1.01 (s, 6H), 1.52 (t, 2H, J=6.41 Hz),2.47 (s, 2H), 2.57 (t, 2H, J=6.41 Hz), 2.73 (d, 3H, J=5.21 Hz), 3.31 (t,2H, J=8.41), 3.58 (t, 2H, J=8.41 Hz), 5.36 (s, 2H), 5.50 (q, 1H, J=5.21Hz), 5.94 (s, 2H), 6.42-6.55 (m, 3H), 7.25 (d, 1H, J=8.41 Hz).

(Step 8) Production ofN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methylacetamide

Under an argon atmosphere, to a solution ofN-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylamine(100 mg, 0.18 mmol) and triethylamine (75 μl, 0.54 mmol) in chloroform(1.5 ml) was added acetyl chloride (19 μl, 0.27 mmol) at roomtemperature, and the mixture was stirred for 2 hr. Water was added tothe reaction mixture, and the mixture was extracted three times withethyl acetate. The combined organic layers were washed successively withwater and saturated brine, and dried over sodium sulfate. Sodium sulfatewas removed by filtration, and the filtrate was concentrated underreduced pressure to giveN-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylacetamide.A solution of the obtainedN-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylacetamidein N,N-dimethylformamide (1.4 ml) was added to tetrabutylammoniumfluoride (1.8 ml, 1.8 mmol) concentrated in advance under reducedpressure. Ethylenediamine (0.7 ml) was added, and the mixture wasstirred with heating at 90° C. for 24 hr. After cooling, water and ethylacetate were added, and the organic layer was separated. Then, theaqueous layer was extracted twice with ethyl acetate. The combinedorganic layers were washed successively with water and saturated brine,is and dried over sodium sulfate. Sodium sulfate was removed byfiltration, and the filtrate was concentrated under reduced pressure.The residue was purified by thin layer silica gel chromatography to givethe title compound (26 mg, yield 42%).

Example 2 Production ofN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-ethylacetamide(Step 1) Production ofN-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-H-indol-6-yl)-N-ethylamine

Under a nitrogen atmosphere, benzylN-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-H-indol-6-yl)-N-ethylcarbamatewas obtained in the same manner as in Example 1, Step 6, from benzyl(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-H-indol-6-yl)carbamateobtained in Example 1, Step 5. To a solution of the obtained benzylN-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-ethylcarbamate(979 mg, 1.4 mmol) in methanol (8 ml) was added 20% palladiumhydroxide-carbon (400 mg). Then, the mixture was stirred under ahydrogen atmosphere at normal pressure for 1.5 hr. After the reaction,the reaction mixture was filtered through celite, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give the title compound (802 mg, yield 100%).¹H-NMR (400 MHz, DMSO-d₆) δ: −0.18 (s, 9H), −0.03 (s, 9H), 0.72 (t, 2H,J=8.0 Hz), 0.89 (t, 2H, J=8 Hz), 1.05 (s, 6H), 1.21-1.24 (m, 3H),1.52-1.57 (m, 2H), 2.50 (s, 2H), 2.56-2.64 (m, 2H), 3.10-3.13 (m, 2H),3.32-3.36 (m, 2H), 3.61 (t, 2H, J=8.0 Hz), 5.39 (s, 2H), 5.96 (s, 2H),6.50 (s, 2H), 6.51-6.54 (m, 1H), 6.61 (brs, 1H), 7.27 (d, 1H, J=8.0 Hz).

(Step 2) Production ofN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-ethylacetamide

In the same manner as in Example 1, Step 8, the title compound (24 mg,yield 35%) was obtained fromN-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-ethylamine (110 mg, 0.19 mmol).

Example 3 Production of benzylN-{2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl}-N-methylcarbamate

A solution of benzylN-(2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylcarbamate(13 g, 19 mmol) obtained in Example 1, Step 6, in N,N-dimethylformamide(102 ml) was added to tetrabutylammonium fluoride (93 ml, 93 mmol)concentrated in advance under reduced pressure, and then ethylenediamine(19 ml) was added. The mixture was stirred with heating at 90° C. for 7hr. After cooling, water and ethyl acetate were added, and the organiclayer was separated. Then, the aqueous layer was extracted with ethylacetate. The combined organic layers were washed successively withwater, 10% aqueous citric acid solution and saturated brine, and driedover sodium sulfate. Sodium sulfate was removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue waspurified by silica gel chromatography to give the title compound (7.2 g,yield 91%).

Example 4 Production of(S)—N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(morpholin-4-yl)propionamide(Step 1) Production ofN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methylamine

Under a nitrogen atmosphere, to a solution of benzylN-{2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1-indol-6-yl}-N-methylcarbamateobtained in Example 3 (7.2 g, 17 mmol) in ethanol (72 ml) were added 10%palladium-carbon (723 mg) and ammonium formate (2.5 g, 39 mmol), and themixture was stirred with heating at 65° C. for 40 min. After cooling,the reaction mixture was filtered through celite, and the filtrate wasconcentrated under reduced pressure. The residue was slurry-washed inwater (300 ml). The precipitate was collected by filtration, washed withwater, and dried under reduced pressure to give the title compound (4.5g, yield 90%). ¹H-NMR (400 MHz, DMSO-d₆) δ: 1.00 (s, 6H), 1.56 (t, 2H,J=6.41 Hz), 2.38 (s, 2H), 2.61 (t, 2H, J=6.41 Hz), 2.69 (d, 3H, J=4.81Hz), 5.24-5.34 (m, 1H), 6.33-6.46 (m, 3H), 7.18 (d, 1H, J=8.41 Hz),10.65 (s, 1H), 12.28 (s, 1H).

(Step 2) Production of(S)—N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(morpholin-4-yl)propionamide

To a solution ofN-{2-(6,6-dimethyl-4,5,6,7-tetrahydro-¹H-indazol-3-yl)-1H-indol-6-yl}-N-methylamine(45 mg, 0.15 mmol) in pyridine (1 ml) were added(S)-2-(morpholin-4-yl)propionic acid obtained in Reference Example 3(110 mg, 0.69 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (106 mg, 0.55 mmol) at room temperature, and the mixturewas stirred for 14 hr. To the reaction mixture were added chloroform andwater, and the organic layer was separated. The organic layer was driedover sodium sulfate. Sodium sulfate was removed by filtration, and thefiltrate was concentrated under reduced pressure. Then, the residue wasdissolved in a mixed solvent of tetrahydrofuran (1 ml) and methanol (1ml). To the solution was added 2 N aqueous sodium hydroxide solution(0.35 ml) at room temperature, and the mixture was stirred for 20 min.To the reaction mixture were added chloroform and water, and the organiclayer was separated. The organic layer was dried over sodium sulfate.Sodium sulfate was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was purified by thinlayer silica gel chromatography to give the title compound (52 mg, yield78%).

Example 5 Production of(S)—N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(morpholin-4-yl)propionamidehydrochloride

To a solution of(S)—N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(morpholin-4-yl)propionamideobtained in Example 4 (100 mg, 0.23 mmol) in ethyl acetate (1 ml) wasadded 4 N hydrochloric acid/ethyl acetate (0.06 ml, 0.24 mmol) at roomtemperature, and the mixture was stirred for 30 min. The precipitatedcrystals were collected by filtration, washed with ethyl acetate, anddried under reduced pressure to give the title compound (75 mg, 69%).

Example 6 Production ofN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(3-oxomorpholin-4-yl)acetamide

Under an argon atmosphere, to a solution ofN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methylamineobtained in Example 4, Step 1 (40 mg, 0.14 mmol) and(3-oxomorpholin-4-yl)acetic acid obtained in Reference Example 4 (76 mg,0.48 mmol) in pyridine (1.3 ml) was added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (91 mg, 0.48mmol) at room temperature, and the mixture was stirred at roomtemperature for 12 hr. Then, the reaction mixture was concentrated underreduced pressure. The residue was dissolved in methanol (1.2 ml), 2 Naqueous sodium hydroxide solution (1.0 ml) was added, and the mixturewas stirred at room temperature for 45 min. Then, to the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. The aqueous layer was extracted twice with ethyl acetate, andthe combined organic layers were washed successively with water andsaturated brine, and dried over sodium sulfate. Sodium sulfate wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography to givethe title compound (40 mg, yield 67%).

Example 7 Production of2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indole-6-carboxylicacid (2-hydroxy-1-methylethyl)methylamide (Step 1) Production of2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylicacid (2-hydroxy-1-methylethyl) amide

To a solution of 2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-H-indole-6-carboxylicacid obtained in Example 1, Step 4 (500 mg, 0.88 mmol) inN,N-dimethylformamide (5 ml) were added 1-hydroxybenzotriazolemonohydrate (161 mg, 1.1 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (202 mg, 1.1mmol) and 2-amino-1-propanol (84 mg, 1.1 mmol) at room temperature, andthe mixture was stirred at room temperature for 7 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. Then, the organic layer was washed successively with waterand saturated brine, and dried over sodium sulfate. Sodium sulfate wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography to givethe title compound (511 mg, yield 93%). ¹H-NMR (400 MHz, DMSO-d₆) δ:−0.22 (s, 9H), −0.03 (s, 9H), 0.68 (t, 2H, J=8.12 Hz), 0.87 (t, 2H,J=8.12 Hz), 1.03 (s, 6H), 1.17 (d, 3H, J=6.72 Hz), 1.54 (t, 2H, J=6.26Hz), 2.50 (s, 2H), 2.62 (t, 2H, J=6.26 Hz), 3.29 (t, 2H, J=8.12 Hz),3.35-3.39 (m, 1H), 3.48-3.53 (m, 1H), 3.60 (t, 2H, J=8.12 Hz), 4.01-4.11(m, 1H), 4.74 (t, 1H, J=5.68 Hz), 5.41 (s, 2H), 6.11 (s, 2H), 6.76 (s,1H), 7.57-7.67 (m, 2H), 8.01 (d, ¹H, J=7.88 Hz), 8.15 (s, 1H).

(Step 2) Production of2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid[2-(tert-butyldiphenylsilyloxy)-1-methylethyl]amide

To a solution of2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylicacid (2-hydroxy-1-methylethyl)amide (265 mg, 0.42 mmol) inN,N-dimethylformamide (2.7 ml) were added imidazole (35 mg, 0.51 mmol)and tert-butyldiphenylsilyl chloride (132 μl, 0.51 mmol) underice-cooling, and the mixture was stirred at room temperature for 8 hr.Then, to the reaction mixture were added water and ethyl acetate, andthe organic layer was separated. Then, the organic layer was washedsuccessively with water and saturated brine, and dried over sodiumsulfate. Sodium sulfate was removed by filtration, and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel chromatography to give the title compound (341 mg, yield 93%).¹H-NMR (400 MHz, DMSO-d₆) δ: −0.24 (s, 9H), −0.03 (s, 9H), 0.64 (t, 2H,J=8.12 Hz), 0.87 (t, 2H, J=8.12 Hz), 1.00 (s, 9H), 1.02 (s, 6H), 1.26(d, 3H, J=6.96 Hz), 1.53 (t, 2H, J=6.38 Hz), 2.50 (s, 2H), 2.60-2.65 (m,2H), 3.24-3.28 (m, 5H), 3.55-3.65 (m, 3H), 3.70-3.77 (m, 1H), 4.23-4.34(m, 1H), 5.41 (s, 2H), 6.09 (s, 2H), 6.76 (s, 1H), 7.36-7.47 (m, 6H),7.58-7.67 (m, 6H), 8.10-8.16 (m, 2H).

(Step 3) Production of2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid[(2-(tert-butyldiphenylsilyloxy)-1-methylethyl]methylamide

Under an argon atmosphere, to a solution of2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid[2-(tert-butyldiphenylsilyloxy)-1-methylethyl]amide (337 mg, 0.39 mmol)in N,N-dimethylformamide (3.4 ml) were added sodium hydride (19 mg, 0.47mmol) and methyl iodide (36 μl, 0.58 mmol) under ice-cooling, and themixture was stirred at room temperature for 3 hr. To the reactionmixture were added water and ethyl acetate, and the organic layer wasseparated. Then, the organic layer was washed successively with waterand saturated brine, and dried over sodium sulfate. Sodium sulfate wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography to givethe title compound (149 mg, yield 44%). ¹H-NMR (400 MHz, DMSO-d₆) δ:−0.23 (s, 9H), −0.05 (s, 9H), 0.59-0.62 (br m, 2H), 0.86 (dd, 2H,J=10.44, 5.80 Hz), 0.98 (s, 9H), 1.02 (s, 6H), 1.08 (br s, 3H), 1.54 (t,2H, J=6.26 Hz), 2.50 (s, 2H), 2.61-2.64 (br m, 2H), 2.83 (s, 3H),3.21-3.29 (m, 2H), 3.38-3.46 (m, 0.6H), 3.54-3.83 (m, 1.4H), 3.58 (t,2H, J=8.00 Hz), 4.04-4.17 (m, 0.6H), 4.72-4.90 (br m, 0.4H), 5.39-5.41(br m, 2H), 5.69-5.83 (m, 0.6H), 5.96-6.09 (m, 1.4H), 6.77 (s, 1H), 7.11(d, 1H, J=9.04 Hz), 7.17-7.75 (m, 12H).

(Step 4) Production of2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indole-6-carboxylicacid (2-hydroxy-1-methylethyl)methylamide

A solution of2-{6,6-dimethyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indole-6-carboxylic acid[2-(tert-butyldiphenylsilyloxy)-methylethyl]methylamide (145 mg, 0.17mmol) in N,N-dimethylformamide (1.2 ml) was added to tetrabutylammoniumfluoride (1.7 ml, 1.7 mmol) concentrated in advance under reducedpressure. Ethylenediamine (0.29 ml) was added, and the mixture wasstirred with heating at 90° C. for 14 hr. After cooling, to the mixturewere added water and ethyl acetate, and the organic layer was separated,washed successively with water, 10% aqueous citric acid solution andsaturated brine, and dried is over sodium sulfate. Sodium sulfate wasremoved by filtration, and the filtrate was concentrated under reducedpressure. The residue was purified by silica gel chromatography to givethe title compound (57 mg, yield 90%).

Example 8 Production ofN-[2-(6-hydroxymethyl-6-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(2-oxopiperidin-1-yl)acetamide(Step 1) Production ofN-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-H-indol-6-yl)-N-methylamine

In the same manner as in Example 1, step 7, the title compound wasobtained from tert-butyl6-benzyloxymethyl-3-iodo-6-methyl-4,5,6,7-tetrahydroindazole-1-carboxylateobtained in Reference Example 5 and 1-tert-butyl 6-methyl2-boronylindole-1,6-dicarboxylate obtained in Reference Example 2.

(Step 2) Production ofN-(2-{6-hydroxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide

To a solution ofN-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methylamine(150 mg, 0.23 mmol) in N,N-dimethylformamide (3 ml) were added(2-oxopiperidin-1-yl)acetic acid obtained in Reference Example 6 (43 mg,0.27 nmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(52 mg, 0.27 nmol) and 1-hydroxybenzotriazole monohydrate (37 mg, 0.27mmol), and the mixture was stirred at room temperature overnight. To thereaction mixture were added ethyl acetate and water, and the organiclayer was separated, washed successively with water and saturated brine,and dried over sodium sulfate. Sodium sulfate was removed by filtration,and the filtrate was concentrated under reduced pressure. The residuewas purified by silica gel chromatography to giveN-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide(158 mg). Under a nitrogen atmosphere, to a solution of the obtainedN-(2-{6-benzyloxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide(158 mg) in a mixed solvent of methanol (0.8 ml) and tetrahydrofuran(0.8 ml) was added 20% palladium hydroxide-carbon (150 mg) at roomtemperature, and the mixture was stirred under a hydrogen atmosphere atnormal pressure for 4 hr. The reaction mixture was filtered throughcelite, and the filtrate was concentrated under reduced pressure to givethe title compound (120 mg, yield 75%). ¹H-NMR (400 MHz, DMSO-d₆) δ:−0.21 (9H, s), −0.04 (9H, s), 0.67 (2H, t, J=7.86 Hz), 0.86 (2H, t,J=8.06 Hz), 0.93 (3H, s), 1.44-1.73 (6H, m), 2.12-2.21 (2H, m), 2.39(1H, d, J=16.52 Hz), 2.59-2.65 (2H, m), 2.59 (1H, d, J=16.52 Hz), 3.22(3H, s), 3.27 (2H, s), 3.31 (2H, t, J=8.06 Hz), 3.59 (2H, t, J=7.86 Hz),3.81 (2H, s), 4.71 (1H, t, J=5.44 Hz), 5.38 (1H, d, J=11.28 Hz), 5.41(1H, d, J=11.69 Hz), 6.02 (1H, d, J=10.48 Hz), 6.07 (1H, d, J=10.88 Hz),6.74 (1H, s), 7.06 (1H, d, J=7.66 Hz), 7.60 (1H, s), 7.64 (1H, d, J=8.06Hz).

(Step 3) Production ofN-[2-(6-hydroxymethyl-6-methyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-2-(2-oxopiperidin-1-yl)acetamide

A solution ofN-(2-{6-hydroxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide(63 mg, 0.09 mmol) in N,N-dimethylformamide (1.5 ml) was added totetrabutylammonium fluoride (0.6 ml, 0.6 mmol) concentrated in advanceunder reduced pressure. Ethylenediamine (0.2 ml) was added, and themixture was stirred with heating at 80° C. overnight. After cooling,water and ethyl acetate were added, and the organic layer was separated.Then, the organic layer was washed successively with water and saturatedbrine, and dried over sodium sulfate. Sodium sulfate was removed byfiltration, and the filtrate was concentrated under reduced pressure.The residue was purified by thin layer silica gel chromatography to givethe title compound (5.5 mg, yield 16%).

The compounds of Examples 9-381 were obtained in the same manner as inthe above-mentioned Examples. The structural formulas and ¹H-NMRspectrum data thereof are shown in Tables 1-1 to 1-78.

In the Tables, the compounds in an optically active form are indicatedwith (an optically active form) under Example No.

¹H-NMR spectra were measured in CDCl₃ or DMSO-D₆, with tetramethylsilaneas an internal standard, and all 6 values are shown in ppm. Unlessspecifically indicated in the Table, the resolution capability wasmeasured at 400 MHz.

The symbols in the Tables mean the following.

s: singletd: doublett: tripletq: quartetdd: double doubletddd: double double doubletbrs: broad singletm: multipletJ: coupling constant

TABLE 1-1 Ex. MS MS No. structural formula NMR (M + H) (M − H) 1

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 1.75 (3H, s), 2.41(2H, s), 2.63-2.69 (2H, m), 3.17 (3H, s), 6.57-6.61 (1H, m), 6.85-6.90(1H, m), 7.21-7.25 (1H, m), 7.52-7.57 (1H, m), 11.41 (1H, br s), 12.54(1H, br s). 337 335 2

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.03 (t, 3H, J = 7.00 Hz), 1.58 (t,2H, J = 6.29 Hz), 2.41 (s, 2H), 2.62-2.73 (m, 2H), 3.66 (q, 2H, J = 7.00Hz), 6.60 (s, 1H), 6.84 (d, 1H, J = 8.05 Hz), 7.21 (s, 1H), 7.55 (d, 1H,J = 8.05 Hz), 11.38 (s, 1H), 12.53 (s, 1H). 351 349 3

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s, 6H), 1.57 (2H, t, 2H, J = 6.01 Hz),2.41 (2H, s, 2H), 2.65 (2H, t, 2H, J = 6.01 Hz), 3.27 (3H, s, 3H), 5.09(2H, s, 2H), 6.56 (1H, s, 1H), 6.89 (1H, d, 1H, J = 8.01 Hz), 7.28-7.34(6H, m, 6H), 7.47 (1H, d, 1H, J = 8.01 Hz), 11.28 (1H, s, 1H), 12.49(1H, s, 1H). 429 427 4

¹H-NMR (DMSO-D₆) δ: 0.95-1.07 (3H, m), 1.01 (6H, s), 1.54-1.61 (2H, m),2.21-2.30 (2H, m), 2.37-2.48 (2H, m), 2.41 (2H, s), 2.62- 2.73 (2H, m),3.16-3.24 (1H, m), 3.19 (3H, s), 3.44- 3.53 (4H, m), 6.57-6.62 (1H, m),6.86-6.93 (1H, m), 7.26-7.32 (1H, m), 7.51-7.57 (1H, m), 11.39 (1H, brs), 12.53 (1H, br s). 436 434 5

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.36 (3H, d, J = 5.8 Hz), 1.54-1.62(2H, m), 2.42 (2H, s), 2.63-2.72 (2H, m), 2.96-3.17 (2H, m), 3.20-3.50(6H, m), 3.65-3.99 (4H, m), 6.63-6.69 (1H, m), 6.96-7.03 (1H, m),7.34-7.40 (1H, m), 7.61-7.66 (1H, m), 10.29 (1H, br s), 11.48 (1H, brs), 12.60 (1H, br s). 436 434

TABLE 1-2 Ex. MS MS No. structural formula NMR (M + H) (M − H) 6

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 2.42 (2H, s),2.63-2.71 (2H, m), 3.21 (3H, s), 3.31-3.37 (2H, m), 3.76-3.81 (2H, m),3.83-3.87 (2H, m), 4.00 (2H, s), 6.57-6.64 (1H, m), 6.90-6.97 (1H, m),7.29-7.33 (1H, m), 7.55-7.61 (1H, m), 11.48 (1H, br s), 12.55 (1H, brs). 436 434 7

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.04-1.10 (3H, m), 1.54-1.60 (2H, m),2.42 (2H, s), 2.65-2.70 (2H, m), 2.82 (3H, s), 3.20-3.54 (2H, m),3.84-4.04 (1H, m), 4.46-4.89 (1H, m), 6.60 (1H, d, J = 1.2 Hz), 7.00(1H, dd, J = 8.1, 1.4 Hz), 7.41-7.43 (1H, m), 7.51 (1H, d, J = 8.1 Hz),11.38 (1H, br s), 12.52 (1H, br s). 381 379 8

¹H-NMR (DMSO-D₆) δ: 0.92 (3H, s), 1.53-1.68 (6H, m), 2.17 (2H, s), 2.29(1H, d, J = 16.12 Hz), 2.54 (1H, d, J = 16.12 Hz), 2.59-2.77 (2H, m),3.19 (3H, s), 3.20-3.25 (2H, m), 3.26 (2H, s), 3.77 (2H, s), 4.62 (1H,s), 6.60 (1H, s), 6.92 (1H, d, J = 7.66 Hz), 7.31 (1H, s), 7.56 (1H, d,J = 7.66 Hz), 11.38 (1H, s), 12.50 (1H, s). 450 448 9

¹H-NMR (DMSO-D₆) δ: 1.02 (s, 6H), 1.59 (t, 2H, J = 6.29 Hz), 2.43 (s,2H), 2.66-2.75 (m, 2H), 6.66 (s, 1H), 7.08 (t, 1H, J = 7.39 Hz), 7.34(t, 2H, J = 7.94 Hz), 7.61 (s, 2H), 7.81 (d, 2H, J = 7.50 Hz), 8.02 (s,1H), 10.15 (s, 1H), 11.64 (s, 1H), 12.61 (s, 1H). 385 383 10

¹H-NMR (DMSO-D₆) δ: 0.99 (s, 6H), 1.55 (t, 2H, J = 6.29 Hz), 2.40 (s,2H), 2.58-2.67 (m, 2H), 3.39 (s, 3H), 6.49 (s, 1H), 6.82 (d, 1H, J =7.94 Hz), 7.07-7.18 (m, 3H), 7.20-7.29 (m, 3H), 7.43 (s, 1H), 11.37 (s,1H), 12.54 (s, 1H). 399 397

TABLE 1-3 Ex. MS MS No. structural formula NMR (M + H) (M − H) 11

¹H-NMR (DMSO-D₆) δ: 0.92 (9H, s), 1.01 (6H, s), 1.56-1.61 (2H, m), 2.42(2H, s), 2.65-2.71 (2H, m), 3.12 (2H, d, J = 6.3 Hz), 6.61 (1H, s),7.47-7.54 (2H, m), 7.92 (1H, s), 8.17 (1H, t, J = 6.3 Hz), 11.51 (1H, brs), 12.57 (1H, br s). 379 377 12

¹H-NMR (DMSO-D₆, 300 MHz) δ: 0.89 (3H, s), 0.91 (3H, s), 1.01 (6H, s),1.55-1.61 (2H, m), 1.81-1.92 (1H, m), 2.42 (2H, s), 2.64-2.71 (2H, m),3.06-3.12 (2H, m), 6.61 (1H, s), 7.45-7.54 (2H, m), 7.90-7.93 (1H, m),8.26-8.32 (1H, m), 8.26-8.32 (1H, m), 11.51 (1H, br s), 12.56 (1H, brs). 365 363 13

¹H-NMR (DMSO-D₆) δ: 0.92 (9H, s), 1.01 (6H, s), 1.09 (3H, d, J = 6.8Hz), 1.53-1.62 (2H, m), 2.42 (2H, s), 2.63- 2.77 (2H, m), 3.96-4.06 (1H,m), 6.61 (1H, s), 7.43-7.57 (2H, m), 7.72-7.80 (1H, m), 7.89 (1H, br s),11.47 (1H, br s), 12.56 (1H, br s). 393 391 14

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 2.21 (3H, s),2.29-2.38 (4H, m), 2.42 (2H, s), 2.64-2.71 (2H, m), 3.44-3.61 (4H, m),6.59-6.62 (1H, m), 6.97-7.01 (1H, m), 7.42-7.46 (1H, m), 7.51-7.55 (1H,m), 11.45 (1H, br s), 12.57 (1H, br s). 392 390 15

¹H-NMR (DMSO-D₆) δ: 0.67- 1.17 (9H, m), 1.01 (6H, s), 1.54-1.62 (2H, m),2.42 (2H, s), 2.64-2.73 (2H, m), 3.03 (3H, s), 3.36 (2H, s), 6.60 (1H,s), 6.96-7.08 (1H, m), 7.41-7.48 (1H, m), 7.49-7.56 (1H, m), 11.38 (1H,br s), 12.55 (1H, br s). 393 391

TABLE 1-4 Ex. MS MS No. structural formula NMR (M + H) (M − H) 16

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.30-1.43 (2H, m), 1.53-1.61 (2H, m),1.69-1.82 (2H, m), 2.42 (2H, s), 2.62-2.73 (2H, m), 3.13-3.22 (2H, m),3.64-4.01 (3H, m), 4.78 (1H, d, J = 4.2 Hz), 6.59-6.63 (1H, m),6.96-7.01 (1H, m), 7.42-7.45 (1H, m), 7.50-7.55 (1H, m), 11.44 (1H, brs), 12.56 (1H, br s). 393 391 17

¹H-NMR (DMSO-D₆, 300 MHz) δ: 0.72-0.95 (6H, m), 1.01 (6H, s), 1.54-1.62(2H, m), 1.93-2.06 (1H, m), 2.42 (2H, s), 2.64-2.72 (2H, m), 2.94 (3H,s), 3.17-3.30 (2H, m), 6.60 (1H, s), 6.94-6.99 (1H, m), 7.37-7.43 (1H,m), 7.50-7.54 (1H, m), 11.41 (1H, br s), 12.55 (1H, br s). 379 377 18

¹H-NMR (DMSO-D₆, 300 MHz) δ: 0.75-0.81 (6H, m), 0.95-1.04 (4H, m), 1.01(6H, s), 1.13-1.27 (2H, m), 1.55-1.61 (2H, m), 2.39-2.43 (2H, m),2.65-2.73 (2H, m), 2.79-2.90 (4H, m), 6.59- 6.62 (1H, m), 6.88-7.00 (1H,m), 7.37-7.40 (1H, m), 7.50-7.54 (1H, m), 11.36 (1H, br s), 12.54 (1H,br s). 407 405 19

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 2.42 (2H, s),2.64-2.72 (2H, m), 3.46-3.57 (4H, m), 3.58-3.67 (4H, m), 6.60-6.63 (1H,m), 6.99-7.04 (1H, m), 7.45-7.48 (1H, m), 7.51-7.56 (1H, m), 11.47 (1H,br s), 12.57 (1H, br s). 379 377 20

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.15 (3H, d, J = 6.7 Hz), 1.55-1.62(2H, m), 2.42 (2H, s), 2.64-2.73 (2H, m), 3.33-3.39 (1H, m), 3.45-3.53(1H, m), 3.98-4.09 (1H, m), 4.71 (1H, br s), 6.61 (1H, br s), 7.46-7.54(2H, m), 7.88-7.95 (2H, m), 11.53 (1H, br s), 12.58 (1H, br s). 367 365

TABLE 1-5 Ex. MS MS No. structural formula NMR (M + H) (M − H) 21

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.15 (3H, d, J = 6.7 Hz), 1.55-1.62(2H, m), 2.42 (2H, s), 2.64-2.72 (2H, m), 3.26-3.31 (1H, m), 3.28 (3H,s), 3.40-3.46 (1H, m), 4.18- 4.26 (1H, m), 6.59-6.65 (1H, m), 7.45-7.55(2H, m), 7.90- 7.94 (1H, m), 8.05 (1H, d, J = 8.1 Hz), 11.53 (1H, br s),12.58 (1H, br s). 381 379 22

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.06-1.14 (3H, m), 1.54-1.61 (2H, m),2.42 (2H, s), 2.64-2.72 (2H, m), 2.81 (3H, s), 3.08-3.56 (5H, m),3.95-4.26 (1H, m), 6.57-6.64 (1H, m), 6.94-6.99 (1H, m), 7.40-7.43 (1H,m), 7.49-7.54 (1H, m), 11.41 (1H, br s), 12.56 (1H, br s). 395 393 23

¹H-NMR (DMSO-D₆) δ: 0.91 (3H, d, J = 7.0 Hz), 0.93 (3H, d, J = 7.0 Hz),1.01 (6H, s), 1.55-1.61 (2H, m), 1.90-2.00 (1H, m), 2.42 (2H, s), 2.65-2.72 (2H, m), 3.53 (2H, t, J = 5.6 Hz), 3.80-3.88 (1H, m), 4.56 (1H, t,J = 5.7 Hz), 6.60- 6.63 (1H, m), 7.48-7.54 (2H, m), 7.74-7.79 (1H, m),7.90- 7.94 (1H, m), 11.52 (1H, br s), 12.58 (1H, br s). 395 393 24

¹H-NMR (DMSO-D₆) δ: 0.91 (3H, d, J = 5.8 Hz), 0.93 (3H, d, J = 5.8 Hz),1.01 (6H, s), 1.54-1.62 (2H, m), 1.85-1.95 (1H, m), 2.42 (2H, s), 2.64-2.73 (2H, m), 3.26 (3H, s), 3.42-3.51 (2H, m), 3.97-4.04 (1H, m),6.59-6.65 (1H, m), 7.48-7.55 (2H, m), 7.88-7.98 (2H, m), 11.51 (1H, brs), 12.57 (1H, br s). 409 407 25

¹H-NMR (DMSO-D₆) δ: 0.68- 1.05 (6H, m), 1.01 (6H, s), 1.55-1.62 (2H, m),1.72-1.97 (1H, m), 2.42 (2H, s), 2.64- 2.71 (2H, m), 2.79-2.87 (3H, m),3.45-3.71 (3H, m), 4.66- 4.85 (1H, m), 6.56-6.61 (1H, m), 6.95-7.07 (1H,m), 7.39- 7.55 (2H, m), 11.36-11.42 (1H, m), 12.52-12.57 (1H, m). 409407

TABLE 1-6 Ex. MS MS No. structural formula NMR (M + H) (M − H) 26

¹H-NMR (DMSO-D₆) δ: 0.69-1.05 (6H, m), 1.00 (6H, s), 1.53-1.61 (2H, m),1.76-1.98 (1H, m), 2.41 (2H, s), 2.63-2.71 (2H, m), 2.75-2.84 (3H, m),3.25-3.31 (3H, m), 3.42-3.65 (3H, m), 6.55- 6.62 (1H, m), 6.91-6.98 (1H,m), 7.37-7.42 (1H, m), 7.46-7.54 (1H, m), 11.37-11.44 (1H, m), 12.54(1H, br s). 423 421 27

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.58 (2H, t, J = 6.40 Hz), 2.41 (2H,s), 2.63-2.69 (2H, m), 6.52 (1H, s), 7.28 (1H, d, J = 8.60 Hz), 7.44(1H, d, J = 8.60 Hz), 7.49-7.63 (3H, m), 7.95-8.05 (3H, m), 10.14 (1H,s), 11.24 (1H, s), 12.46 (1H, s). 385 383 28

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.07-1.13 (3H, m), 1.53-1.60 (2H, m),2.28-2.35 (2H, m), 2.40 (2H, s), 2.62-2.69 (2H, m), 6.46-6.50 (1H, m),7.03-7.08 (1H, m), 7.35-7.39 (1H, m), 7.87- 7.91 (1H, m), 9.72 (1H, brs), 11.11 (1H, br s), 12.41 (1H, br s). 337 335 29

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.52-1.59 (2H, m), 2.40 (2H, s),2.60-2.69 (2H, m), 5.69 (2H, br s), 6.41-6.45 (1H, m), 6.80-6.86 (1H,m), 7.29-7.34 (1H, m), 7.65- 7.68 (1H, m), 8.36 (1H, br s), 11.00 (1H,br s), 12.40 (1H, br s). 324 322 30

¹H-NMR (DMSO-D₆) δ: 0.99 (6H, s), 1.55 (2H, t, J = 6.06 Hz), 2.39 (2H,s), 2.58-2.66 (2H, m), 3.40 (3H, s), 6.49 (1H, s), 6.81 (1H, d, J = 8.60Hz), 7.07 (1H, s), 7.11- 7.22 (3H, m), 7.23-7.30 (2H, m), 7.38 (1H, d, J= 8.38 Hz), 11.22 (1H, s), 12.48 (1H, s). 399 397 31

¹H-NMR (DMSO-D₆) δ: 0.99 (6H, s), 1.53-1.58 (2H, m), 2.39 (2H, s),2.59-2.65 (2H, m), 3.43 (3H, s), 6.50 (1H, s), 6.84-6.88 (1H, m),7.09-7.12 (1H, m), 7.36-7.42 (2H, m), 7.50-7.59 (2H, m), 7.60-7.65 (1H,m), 11.25 (1H, br s), 12.49 (1H, br s). 467 465

TABLE 1-7 Ex. MS MS No. structural formula NMR (M + H) (M − H) 32

¹H-NMR (DMSO-D₆, 300 MHz) δ: 0.91 (3H, t, J = 7.5 Hz), 1.01 (6H, s),1.54-1.61 (2H, m), 1.95- 2.05 (2H, m), 2.41 (2H, s), 2.62-2.71 (2H, m),3.18 (3H, s), 6.57-6.61 (1H, m), 6.84-6.89 (1H, m), 7.21- 7.24 (1H, m),7.51-7.57 (1H, m), 11.39 (1H, br s), 12.53 (1H, br s). 351 349 33

¹H-NMR (DMSO-D₆) 300 MHz) δ: 1.01 (6H, s), 1.25-1.36 (2H, m), 1.41- 1.71(8H, m), 2.41 (2H, s), 2.52-2.60 (1H, m), 2.64-2.70 (2H, m), 3.18 (3H,s), 6.57-6.62 (1H, m), 6.83-6.89 (1H, m), 7.22-7.26 (1H, m), 7.51- 7.57(1H, m), 11.38 (1H, br s), 12.54 (1H, br s). 391 389 34

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.03 (3H, d, J = 6.8 Hz), 1.55-1.61(2H, m), 2.41 (2H, s), 2.64-2.70 (2H, m), 3.20 (3H, s), 4.00-4.15 (2H,m), 6.58-6.64 (1H, m), 6.86-6.91 (1H, m), 7.22- 7.30 (1H, m), 7.52-7.59(1H, m), 11.41 (1H, br s), 12.53 (1H, br s). 367 365 35

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 2.42 (2H, s),2.63-2.71 (2H, m), 3.21 (3H, s), 3.66- 3.76 (2H, m), 4.48 (1H, t, J =5.7 Hz), 6.57-6.63 (1H, m), 6.84-6.90 (1H, m), 7.21-7.27 (1H, m),7.50-7.58 (1H, m), 11.42 (1H, br s), 12.54 (1H, br s). 353 351 36

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 2.41 (2H, s),2.63-2.72 (2H, m), 3.14- 3.24 (6H, m), 3.73 (2H, s), 6.57-6.63 (1H, m),6.85-6.92 (1H, m), 7.23- 7.27 (1H, m), 7.52-7.58 (1H, m), 11.42 (1H, brs), 12.54 (1H, br s). 367 365

TABLE 1-8 Ex. MS MS No. structural formula NMR (M + H) (M − H) 37

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.20 (6H, br s), 1.54-1.61 (2H, m),2.41 (2H, s), 2.63-2.71 (2H, m), 3.30 (3H, s), 4.88 (1H, br s), 6.54-6.62 (1H, m), 6.82- 6.90 (1H, m), 7.21-7.28 (1H, m), 7.46-7.51 (1H, m),11.32 (1H, br s), 12.51 (1H, br s). 381 379 38

¹H-NMR (DMSO-D₆) δ: 0.74 (3H, t, J = 7.4 Hz), 1.01 (6H, s), 1.40-1.50(2H, m), 1.55-1.61 (2H, m), 1.95-2.02 (2H, m), 2.42 (2H, s), 2.64-2.69(2H, m), 3.18 (3H, s), 6.57-6.61 (1H, m), 6.82- 6.88 (1H, m), 7.20-7.23(1H, m), 7.52-7.57 (1H, m), 11.40 (1H, br s), 12.54 (1H, br s). 365 36339

¹H-NMR (DMSO-D₆) δ: 0.90 (3H, s), 0.92 (3H, s), 1.01 (6H, s), 1.55-1.61(2H, m), 2.42 (2H, s), 2.45-2.53 (1H, m), 2.64- 2.70 (2H, m), 3.16 (3H,s), 6.58-6.62 (1H, m), 6.85-6.90 (1H, m), 7.21- 7.26 (1H, m), 7.53-7.58(1H, m), 11.39 (1H, br s), 12.54 (1H, br s). 365 363 40

¹H-NMR (DMSO-D₆) δ: 0.75 (3H, s), 0.77 (3H, s), 1.01 (6H, s), 1.55-1.61(2H, m), 1.89-1.93 (2H, m), 1.94-2.02 (1H, m), 2.42 (2H, s), 2.64-2.70(2H, m), 3.18 (3H, s), 6.57-6.61 (1H, m), 6.81- 6.86 (1H, m), 7.18-7.22(1H, m), 7.52-7.58 (1H, m), 11.40 (1H, br s), 12.54 (1H, br s). 379 37741

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.08 (3H, d, J = 6.4 Hz), 1.54- 1.61(2H, m), 2.42 (2H, s), 2.64-2.70 (2H, m), 3.04 (3H, s), 3.21 (3H, s),3.79 (1H, q, J = 6.3 Hz), 6.58-6.62 (1H, m), 6.86-6.91 (1H, m),7.24-7.28 (1H, m), 7.54-7.60 (1H, m), 11.40 (1H, br s), 12.53-12.55 (1H,br m). 381 379

TABLE 1-9 Ex. MS MS No. structural formula NMR (M + H) (M − H) 42

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.12-1.49 (6H, m), 1.53-1.63 (2H, m),2.41 (2H, s), 2.63- 2.69 (2H, m), 2.93-3.58 (6H, m), 6.54-6.58 (1H, m),6.80-6.86 (1H, m), 7.18-7.25 (1H, m), 7.44- 7.49 (1H,m), 11.29 (1H, brs), 12.51 (1H, br s). 395 393 43

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 2.41 (2H, s),2.64-2.72 (2H, m), 3.18- 3.27 (1H, m), 3.20 (3H, s), 3.40-3.48 (1H, m),3.97-4.04 (1H, m), 4.50-4.56 (1H, m), 4.77 (1H, d, J = 6.6 Hz), 6.56-6.64 (1H, m), 6.87-6.93 (1H, m), 7.26-7.31 (1H, m), 7.51-7.57 (1H, m),11.42 (1H, br s), 12.53 (1H, br s). 383 381 44

¹H-NMR (DMSO-D₆) δ: 0.97-1.05 (3H, m), 1.01 (6H, s), 1.55-1.60 (2H, m),2.42 (2H, s), 2.64- 2.70 (2H, m), 3.18 (3H, s), 3.29-3.37 (2H, m), 3.75(2H, s), 6.58-6.61 (1H, m), 6.85-6.91 (1H, m), 7.22-7.27 (1H, m),7.52-7.55 (1H, m), 11.43 (1H, br s), 12.54 (1H, br s). 381 379 45

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 2.42 (2H, s),2.64-2.69 (2H, m), 3.23 (3H,s), 4.41 (2H, s), 6.60-6.63 (1H, m), 6.71-6.78 (2H, m), 6.87-6.93 (1H, m), 6.99-7.04 (1H, m), 7.20-7.27 (2H, m),7.36-7.40 (1H, m), 7.56- 7.61 (1H, m), 11.47 (1H, br s), 12.55 (1H, brs). 429 427 46

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.03 (3H, d, J = 6.9 Hz), 1.56-1.61(2H, m), 2.41 (2H, s), 2.64-2.71 (2H, m), 3.20 (3H, s), 4.01-4.10 (1H,m), 4.73 (1H, d, J = 7.3 Hz), 6.57-6.62 (1H, m), 6.85-6.91 (1H, m),7.23- 7.28 (1H, m), 7.53-7.58 (1H, m), 11.43 (1H, br s), 12.54 (1H, brs). 367 365

TABLE 1-10 Ex. MS MS No. structural formula NMR (M + H) (M − H) 47

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.62 (2H, m), 2.39-2.44 (2H, m),2.64-2.70 (2H, m), 3.08 (6H, s), 3.22 (3H, s), 3.30-3.38 (1H, m), 3.43-3.52 (1H, m), 3.86-3.94 (1H, m), 6.58-6.66 (1H, m), 6.87-6.98 (1H, m),7.25-7.34 (1H, m), 7.53- 7.63 (1H, m), 11.46 (1H, br s), 12.55 (1H, brs). 411 409 48

¹H-NMR DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 2.41 (2H, s),2.63-2.71 (2H, m), 3.10 (3H,s), 3.21 (3H, s), 3.35-3.43 (1H, m), 3.45-3.54 (1H, m), 3.75-3.81 (1H, m), 4.68-4.74 (1H, m), 6.58-6.64 (1H, m),6.87-6.93 (1H, m), 7.25- 7.32 (1H, m), 7.54-7.63 (1H, m), 11.43 (1H, brs), 12.55 (1H, br s). 397 395 49

¹H-NMR (DMSO-D₆) δ: 0.66 (3H, t, J = 7.4 Hz), 1.01 (6H, s), 1.26-1.38(1H, m), 1.41-1.54 (1H, m), 1.55-1.61 (2H, m), 2.42 (2H, s), 2.63-2.70(2H, m), 3.21 (3H, s), 3.82-3.90 (1H, m), 4.67 (1H, d, J = 7.7 Hz),6.58- 6.62 (1H, m), 6.84-6.90 (1H, m), 7.21-7.30 (1H, m), 7.51-7.61 (1H,m), 11.43 (1H, br s), 12.55 (1H, br s). 381 379 50

¹H-NMR (DMSO-D₆) δ: 0.61-0.77 (3H, m), 1.01 (6H, s), 1.39-1.65 (4H, m),2.42 (2H, s), 2.63- 2.70 (2H, m), 3.09 (3H, s), 3.22 (3H, s), 3.58- 3.67(1H, m), 6.57- 6.67 (1H, m), 6.82-6.94 (1H, m), 7.21-7.31 (1H, m),7.53-7.63 (1H, m), 11.42 (1H, br s), 12.55 (1H, br s). 395 393 51

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.53-1.61 (2H, m), 2.41 (2H, s),2.63-2.69 (2H, m), 3.17 (3H, s), 4.17 (2H, d, J = 6.0 Hz), 6.13 (1H, t,J = 6.1 Hz), 6.55-6.59 (1H, m), 6.85-6.90 (1H, m), 7.16-7.23 (3H, m),7.25- 7.31 (3H, m), 7.50-7.55 (1H, m), 11.35 (1H, br s), 12.51 (1H, brs). 428 426

TABLE 1-11 Ex. MS MS No. structural formula NMR (M + H) (M − H) 52

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.52-1.69 (3H, m), 1.70-1.80 (1H, m),1.84-1.96 (2H, m), 2.41 (2H, s), 2.62-2.71 (2H, m), 3.19 (3H, s),3.59-3.66 (1H, m), 3.77- 3.85 (1H, m), 4.15-4.23 (1H, m), 6.56-6.63 (1H,m), 6.84-6.93 (1H, m), 7.22-7.29 (1H, m), 7.51- 7.59 (1H, m), 11.42 (1H,br s), 12.54 (1H, br s). 393 391 53

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.53-1.61 (2H, m), 2.41 (2H, s),2.62-2.73 (2H, m), 3.07 (3H, s), 3.13-3.26 (1H, m), 3.21 (3H, s), 3.38-3.45 (1H, m), 4.08-4.16 (1H, m), 4.98 (1H, d, J = 7.3 Hz), 6.57-6.63(1H, m), 6.85-6.92 (1H, m), 7.25-7.31 (1H, m), 7.52- 7.59 (1H, m), 11.44(1H, br s), 12.53 (1H, br s). 397 395 54

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 2.41 (2H, s),2.62-2.69 (2H, m), 3.14 (3H, s), 5.47 (2H, br s), 6.54-6.58 (1H, m),6.83- 6.88 (1H, m), 7.21-7.25 (1H, m), 7.48-7.54 (1H, m), 11.32 (1H, brs), 12.51 (1H, br s). 338 336 55

¹H-NMR (DMSO-D₆) δ: 0.79 (3H, t, J = 7.5 Hz), 1.01 (6H, s), 1.37-1.46(2H, m), 1.55-1.61 (2H, m), 2.41 (2H, s), 2.64- 2.69 (2H, m), 3.19 (3H,s),3.22-3.27 (2H, m), 3.76 (2H, s), 6.58-6.61 (1H, m), 6.85-6.90 (1H,m), 7.23-7.26 (1H, m), 7.51- 7.56 (1H, m), 11.41 (1H, br s), 12.54 (1H,br s). 395 393 56

¹H-NMR (DMSO-D₆) δ: 0.94 (3H, s), 0.96 (3H, s), 1.01 (6H, s), 1.55-1.61(2H, m), 2.41 (2H, s), 2.64-2.71 (2H, m), 3.18 (3H, s), 3.38-3.47 (1H,m), 3.75 (2H, s), 6.57- 6.63 (1H, m), 6.85-6.91 (1H, m), 7.23-7.27 (1H,m), 7.51-7.57 (1H, m), 11.41 (1H, br s), 12.53 (1H, br s). 395 393

TABLE 1-12 Ex. MS MS No. structural formula NMR (M + H) (M − H) 57

¹H-NMR (DMSO-D₆) δ: 0.98 (6H, s), 1.51-1.57 (2H, m), 2.39 (2H, s),2.58-2.63 (2H, m), 3.43 (3H, s), 6.46-6.51 (1H, m), 6.82-6.88 (1H, m),7.20-7.23 (1H, m), 7.33- 7.39 (1H, m), 7.48-7.54 (2H, m), 7.63-7.68 (1H,m), 7.77-7.82 (2H, m), 11.38 (1H, br s), 12.51 (1H, br s). 427 425 58

¹H-NMR (DMSO-D₆) δ: 0.86 (3H, d, J = 6.9 Hz), 1.01 (6H, s), 1.55-1.61(2H, m), 2.41 (2H, s), 2.62-2.73 (3H, m), 3.04- 3.09 (1H, m), 3.11 (3H,s), 3.18 (3H, br s), 3.45- 3.50 (1H, m), 6.58-6.62 (1H, m), 6.83-6.89(1H, m), 7.23-7.27 (1H, m), 7.52-7.58 (1H, m), 11.40 (1H, br s), 12.53(1H, br s). 395 393 59

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.54-1.59 (2H, m), 2.22 (3H, s), 2.40(2H, s), 2.62-2.68 (2H, m), 3.38 (3H, s), 6.02 (1H, s), 6.52-6.56 (1H,m), 6.81-6.86 (1H, m), 7.15-7.18 (1H, m), 7.41-7.45 (1H, m), 11.35 (1H,br s), 12.52 (1H, br s). 404 402 60

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.22-1.38 (1H, m), 1.39-1.48 (2H, m),1.55-1.71 (4H, m), 2.42 (2H, s), 2.64-2.70 (2H, m), 2.92-3.00 (2H, m),3.17 (3H, s), 3.69- 3.77 (2H, m), 6.59-6.62 (1H, m), 6.86-6.91 (1H, m),7.23-7.26 (1H, m), 7.54-7.59 (1H, m), 11.38 (1H, br s), 12.54 (1H, brs). 407 405 61

¹H-NMR (DMSO-D₆) δ: 0.87 (3H, d, J = 6.9 Hz), 1.01 (6H, s), 1.55-1.60(2H, m), 2.41 (2H, s), 2.52-2.58 (1H, m), 2.64- 2.70 (2H, m), 3.12-3.19(1H, m), 3.18 (3H, s), 3.49-3.56 (1H, m), 4.51 (1H, t, J = 5.4 Hz),6.58- 6.62 (1H, m), 6.86-6.90 (1H, m), 7.25-7.28 (1H, m), 7.53-7.56 (1H,m), 11.37 (1H, br s), 12.52 (1H, br s). 381 379

TABLE 1-13 Ex. MS MS No. structural formula NMR (M + H) (M − H) 62

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 2.21-2.27 (2H, m),2.41 (2H, s), 2.63- 2.70 (2H, m), 3.12 (3H, s), 3.18 (3H, s), 3.44-3.50(2H, m), 6.57-6.63 (1H, m), 6.83-6.90 (1H, m), 7.20-7.26 (1H, m), 7.51-7.57 (1H, m), 11.42 (1H, br s), 12.54 (1H, br s). 381 379 63

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 2.15-2.23 (2H, m),2.41 (2H, s), 2.62- 2.72 (2H, m), 3.18 (3H, s), 3.50-3.59 (2H, m), 4.39(1H, t, J = 5.1 Hz), 6.57-6.63 (1H, m), 6.84- 6.91 (1H, m), 7.21-7.27(1H, m), 7.51-7.59 (1H, m), 11.42 (1H, br s), 12.54 (1H, br s). 367 36564

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.34-1.46 (1H, m), 1.51-1.62 (5H, m),1.92 (3H, s), 2.15- 2.23 (1H, m), 2.42 (2H, s), 2.44-2.53 (1H, m),2.63-2.76 (3H, m), 3.17 (3H, s), 3.65-3.73 (1H, m), 4.21-4.29 (1H, m),6.57-6.64 (1H, m), 6.86- 6.94 (1H, m), 7.23-7.28 (1H, m), 7.54-7.59 (1H,m), 11.40 (1H, br s), 12.54 (1H, br s). 448 446 65

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.40-1.54 (4H, m), 1.56-1.68 (4H, m),2.00 (3H, s), 2.09- 2.19 (1H, m), 2.42 (2H, s), 2.61-2.72 (4H, m), 3.16(3H, s), 6.57-6.64 (1H, m), 6.84-6.91 (1H, m), 7.20-7.27 (1H, m),7.52-7.58 (1H, m), 11.38 (1H, br s), 12.54 (1H, br s). 420 418 66

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 1.69-1.79 (1H, m),1.96-2.06 (1H, m), 2.42 (2H, s), 2.63-2.74 (2H, m), 2.85-2.94 (1H, m),3.20 (3H, s), 3.47- 3.54 (1H, m), 3.55-3.65 (2H, m), 3.66-3.73 (1H, m),6.57-6.63 (1H, m), 6.85-6.92 (1H, m), 7.21- 7.27 (1H, m), 7.54-7.59 (1H,m), 11.42 (1H, br s), 12.54 (1H, br s). 393 391

TABLE 1-14 Ex. MS MS No. structural formula NMR (M + H) (M − H) 67

¹H-NMR (DMSO-D₆) δ: 0.64 (3H, d, J = 6.9 Hz), 0.72 (3H, d, J = 6.9 Hz),1.01 (6H, s), 1.55-1.61 (2H, m), 1.70-1.80 (1H, m), 2.42 (2H, s), 2.63-2.71 (2H, m), 3.22 (3H, s), 3.63-3.70 (1H, m), 4.59 (1H, d, J = 8.1 Hz),6.57-6.62 (1H, m), 6.83- 6.89 (1H, m), 7.22-7.27 (1H, m), 7.52-7.57 (1H,m), 11.37 (1H, br s), 12.51 (1H, br s). 395 393 68

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.56-1.61 (2H, m), 2.42 (2H, s),2.64-2.71 (2H, m), 3.20 (3H, s), 5.05 (1H, d, J = 7.3 Hz), 5.49 (1H, d,J = 7.3 Hz), 6.58-6.63 (1H, m), 6.67-6.75 (1H, m), 6.98-7.03 (2H, m),7.11- 7.17 (1H, m), 7.18-7.23 (3H, m), 7.47-7.54 (1H, m), 11.43 (1H, brs), 12.54 (1H, br s). 429 427 69

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.08 (6H, s), 1.56-1.60 (2H, m), 2.18(2H, s), 2.41 (2H, s), 2.65-2.69 (2H, m), 3.20 (3H, s), 4.94 (1H, s),6.59-6.61 (1H, m), 6.83- 6.87 (1H, m), 7.21-7.23 (1H, m), 7.53-7.57 (1H,m), 11.42 (1H, br s), 12.54 (1H, br s). 395 393 70

¹H-NMR (DMSO-D₆) δ: 0.91 (3H, t, J = 7.5 Hz), 1.01 (6H, s), 1.56-1.61(2H, m), 1.97-2.05 (2H, m), 2.43 (2H, s), 2.66- 2.71 (2H, m), 3.18 (3H,s), 6.63-6.66 (1H, m), 6.85-6.90 (1H, m), 7.24- 7.27 (1H, m), 7.52-7.58(1H, m), 11.41 (1H, br s). 351 349, 385 71

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.26-1.36 (1H, m), 1.54-1.60 (2H, m),1.62-1.76 (2H, m), 1.87-1.97 (1H, m), 2.05- 2.13 (1H, m), 2.28-2.36 (1H,m), 2.41 (2H, s), 2.63-2.71 (2H, m), 3.18 (3H, s), 3.47-3.53 (1H, m),3.55-3.61 (1H, m), 4.05-4.13 (1H, m), 6.57- 6.62 (1H, m), 6.83-6.88 (1H,m), 7.20-7.26 (1H, m), 7.52-7.56 (1H, m), 11.41 (1H, br s), 12.53 (1H,br s). 407 405

TABLE 1-15 Ex. MS MS No. structural formula NMR (M + H) (M − H) 72

¹H-NMR (DMSO-D₆) δ: 0.63-0.76 (2H, m), 0.92- 1.06 (1H, m), 1.01 (6H, s),1.09-1.21 (2H, m), 1.49-1.62 (7H, m), 1.64- 1.75 (1H, m), 1.87-1.93 (2H,m), 2.41 (2H, s), 2.63-2.70 (2H, m), 3.18 (3H, s), 6.56-6.62 (1H, m),6.78-6.85 (1H, m), 7.17-7.21 (1H, m), 7.51- 7.57 (1H, m), 11.39 (1H, brs), 12.53 (1H, br s). 419 417 73

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.62 (2H, m), 2.42 (2H, s),2.63-2.73 (2H, m), 3.23 (3H, s), 4.48 (2H, s), 5.97-6.03 (2H, m), 6.60-6.67 (1H, m), 7.01-7.07 (1H, m), 7.38-7.42 (1H, m), 7.44-7.50 (2H, m),7.58-7.63 (1H, m), 11.56 (1H, br s), 12.57 (1H, br s). 430 428 74

¹H-NMR (DMSO-D₆) δ: 0.62-1.06 (2H, m), 1.01 (6H, s), 1.28-1.49 (2H, m),1.55-1.93 (6H, m), 2.10-2.29 (1H, m), 2.41 (2H, s), 2.64-2.71 (2H, m),3.12-3.18 (6H, m), 3.19-3.24 (1H, m), 6.58- 6.63 (1H, m), 6.85-6.89 435433 (1H, m), 7.21-7.27 (1H, m), 7.52-7.58 (1H, m), 11.36 (1H, br s),12.53 (1H, br s). 75

¹H-NMR (DMSO-D₆) δ: 0.95 (6H, s), 1.01 (6H, s), 1.55-1.61 (2H, m), 2.42(2H, s), 2.64-2.70 (2H, m), 3.11 (2H, s), 3.13 (3H, s), 4.36 (2H, s),6.59-6.63 (1H, m), 6.84-6.88 (1H, m), 7.25- 7.31 (4H, m), 7.32-7.37 (2H,m), 7.49-7.53 (1H, m), 11.41 (1H, br s), 12.53 (1H, br s). 485 483 76

¹H-NMR (DMSO-D₆) δ: 0.85 (6H, s), 1.01 (6H, s), 1.54-1.62 (2H, m), 2.41(2H, s), 2.61-2.75 (2H, m), 3.13 (3H, s), 3.23 (2H, d, J = 5.6 Hz),4.48-4.56 (1H, m), 6.55- 6.64 (1H, m), 6.85-6.95 (1H, m), 7.24-7.32 (1H,m), 7.48-7.56 (1H, m), 11.37 (1H, br s), 12.53 (1H, br s). 395 393

TABLE 1-16 Ex. MS MS No. structural formula NMR (M + H) (M − H) 77

¹H-NMR (DMSO-D₆) δ: 0.62-0.86 (2H, m), 0.94- 1.13 (3H, m), 1.01 (6H, s),1.26-1.33 (1H, m), 1.44- 1.64 (6H, m), 1.66-1.74 (1H, m), 2.41 (2H, s),2.64-2.70 (2H, m), 3.21 (3H, s), 3.62-3.67 (1H, m), 4.65 (1H, d, J = 7.7Hz), 6.58-6.63 (1H, m), 6.83-6.88 (1H, m), 7.22- 7.27 (1H, m), 7.52-7.57(1H, m), 11.41 (1H, br s), 12.53 (1H, br s). 435 433 78

¹H-NMR (DMSO-D₆) δ: 0.61-0.86 (2H, m), 0.92- 1.15 (3H, m), 1.01 (6H, s),1.26-1.33 (1H, m), 1.44- 1.63 (6H, m), 1.67-1.74 (1H, m), 2.42 (2H, s),2.64-2.70 (2H, m), 3.21 (3H, s), 3.62-3.67 (1H, m), 4.65 (1H, d, J = 7.7Hz), 6.57-6.62 (1H, m), 6.83-6.88 (1H, m), 7.21- 7.26 (1H, m), 7.53-7.57(1H, m), 11.42 (1H, br s), 12.54 (1H, br s). 435 433 79

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.24-1.33 (2H, m), 1.36-1.47 (4H, m),1.55-1.61 (2H, m), 2.17-2.35 (4H, m), 2.41 (2H, s), 2.63-2.71 (2H, m),2.78-2.87 (2H, m), 3.17 (3H, s), 6.57-6.61 (1H, m), 6.83-6.89 (1H, m),7.21-7.27 (1H, m), 7.50-7.56 (1H, m), 11.40 (1H, br s), 12.53 (1H, brs). 420 418 80

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 2.27-2.37 (4H, m),2.41 (2H, s), 2.63- 2.71 (2H, m), 2.86 (2H, s), 3.18 (3H, s), 3.46-3.53(4H, m), 6.57-6.64 (1H, m), 6.85-6.92 (1H, m), 7.24-7.31 (1H, m), 7.51-7.57 (1H, m), 11.41 (1H, br s), 12.53 (1H, br s). 422 420 81

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.27-1.39 (2H, m), 1.55-1.61 (2H, m),1.68-1.77 (2H, m), 2.00-2.10 (2H, m), 2.41 (2H, s), 2.52-2.59 (2H, m),2.64-2.71 (2H, m), 2.84 (2H, s), 3.01-3.09 (1H, m), 3.17 (6H, s),6.56-6.62 (1H, m), 6.82-6.90 (1H, m), 7.22-7.28 (1H, m), 7.49- 7.57 (1H,m), 11.41 (1H, br s), 12.53 (1H, br s). 450 448

TABLE 1-17 Ex. MS MS No. structural formula NMR (M + H) (M − H) 82

¹H-NMR (DMSO-D₆) δ: 0.62-0.74 (2H, m), 1.01 (6H, s), 1.37-1.50 (2H, m),1.56-1.61 (2H, m), 1.63-1.70 (2H, m), 1.86- 1.94 (2H, m), 2.10-2.20 (1H,m), 2.41 (2H, s), 2.64-2.70 (2H, m), 2.95- 3.05 (1H, m), 3.12-3.19 435433 (6H, m), 6.58-6.64 (1H, m), 6.85-6.91 (1H, m), 7.21-7.27 (1H, m),7.53- 7.58 (1H, m), 11.36 (1H, br s), 12.53 (1H, br s). 83

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 1.85-1.93 (2H, m),2.14-2.21 (2H, m), 2.41 (2H, s), 2.64-2.70 (2H, m), 3.19 (3H,s),3.29-3.37 (1H, m), 3.71 (2H, s), 6.59-6.64 (1H, m), 6.90-6.96 (1H, m),7.28-7.33 (1H, m), 7.55- 7.60 (1H, m), 11.46 (1H, br s), 12.54 (1H, brs). 420 418 84

¹H-NMR (DMSO-D₆) δ: 0.97-1.09 (2H, m), 1.01 (6H, s), 1.23-1.34 (2H, m),1.49-1.62 (4H, m), 1.74-1.86 (2H, m), 2.16- 2.26 (1H, m), 2.41 (2H, s),2.63-2.71 (2H, m), 3.15 (3H, s), 3.59-3.67 (1H, m), 4.19-4.26 (1H, m),6.56-6.63 (1H, m), 6.82-6.89 (1H, m), 7.19- 7.26 (1H, m), 7.51-7.57 (1H,m), 11.36 (1H, br s), 12.53 (1H, br s). 421 419 85

¹H-NMR (DMSO-D₆) δ: 0.94-1.06 (8H, m), 1.28- 1.37 (2H, m), 1.55-1.60(2H, m), 1.61-1.79 (4H, m), 2.20-2.29 (1H, m), 2.41 (2H, s), 2.62-2.71(2H, m), 3.15 (6H, s), 3.19-3.24 (1H, m),6.57- 6.64 (1H, m), 6.83-6.89435 433 (1H, m), 7.20-7.27 (1H, m), 7.52-7.58 (1H, m), 11.36 (1H, br s),12.53 (1H, br s). 86

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 2.41 (2H, s),2.63-2.71 (2H, m), 3.23 (3H, s), 4.53 (2H, s), 6.59-6.66 (1H, m),7.01-7.08 (1H, m), 7.17-7.22 (1H, m), 7.25-7.31 (1H, m), 7.37-7.44 (1H,m), 7.57-7.63 (1H, m), 8.12-8.17 (2H, m), 11.49 (1H, br s), 12.55 (1H,br s). 430 428

TABLE 1-18 Ex. MS MS No. structural formula NMR (M + H) (M − H) 87

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.53-1.61 (2H, m), 1.65-1.83 (2H, m),2.41 (2H, s), 2.61- 2.72 (2H, m), 3.19 (3H, s), 3.48-3.66 (4H, m),3.73-3.84 (2H, m), 3.99- 4.07 (1H, m), 6.54-6.66 (1H, m), 6.84-6.94 (1H,m), 7.21-7.33 (1H, m), 7.50-7.58 (1H, m), 11.43 (1H, br s), 12.55 (1H,br s). 423 421 88

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.22-1.33 (2H, m), 1.54-1.61 (2H, m),1.65-1.74 (2H, m), 2.41 (2H, s), 2.62-2.71 (2H, m), 3.19 (3H, s),3.21-3.27 (2H, m), 3.35- 3.44 (1H, m), 3.66-3.74 (2H, m), 3.82 (2H, s),6.57-6.64 (1H, m), 6.86- 6.93 (1H, m), 7.24-7.30 (1H, m), 7.51-7.57 (1H,m), 11.43 (1H, br s), 12.54 (1H, br s). 437 435 89

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.63 (2H, m), 2.42 (2H, s),2.64-2.73 (2H, m), 3.23 (3H, s), 4.59 (2H, s), 6.60-6.67 (1H, m), 6.82(1H, s), 7.01-7.07 (1H, m), 7.04 (1H, s), 7.36- 7.42 (1H, m), 7.48 (1H,s), 7.57-7.65 (1H, m), 11.53 (1H, br s), 12.56 (1H, br s). 403 401 90

¹H-NMR (DMSO-D₆) δ: 0.90-1.04 (1H, m), 1.01 (6H, s), 1.22-1.47 (3H, m),1.48-1.61 (3H, m), 1.63-1.71 (1H, m), 2.00- 2.07 (1H, m), 2.18-2.26 (1H,m), 2.42 (2H, s), 2.63-2.71 (2H, m), 3.18 (3H, s), 3.22-3.30 (1H, m),3.59-3.67 (1H, m), 3.72-3.78 (1H, m), 6.56- 6.63 (1H, m), 6.79-6.87 (1H,m), 7.18-7.25 (1H, m), 7.51-7.57 (1H, m), 11.40 (1H, br s), 12.54 (1H,br s). 421 419 91

¹H-NMR (DMSO-D₆) δ: 0.89 (9H, s), 1.01 (6H, s), 1.55-1.61 (2H, m), 1.98(2H, s), 2.41 (2H, s), 2.64-2.71 (2H, m), 3.17 (3H, s), 6.55-6.63 (1H,m), 6.77-6.85 (1H, m), 7.16-7.23 (1H, m), 7.51- 7.57 (1H, m), 11.38 (1H,br s), 12.53 (1H, br s). 393 391

TABLE 1-19 Ex. MS MS No. structural formula NMR (M + H) (M − H) 92

¹H-NMR (DMSO-D₆) δ: 0.87-0.98 (2H, m), 1.01 (6H, s), 1.35-1.46 (4H, m),1.55-1.61 (2H, m), 1.61-1.70 (2H, m), 2.00- 2.06 (2H, m), 2.08-2.17 (1H,m), 2.41 (2H, s), 2.64-2.71 (2H, m), 3.18 (3H, s), 6.56-6.62 (1H, m),6.80-6.87 (1H, m), 7.18-7.24 (1H, m), 7.51- 7.57 (1H, m), 11.37 (1H, brs), 12.53 (1H, br s). 405 403 93

¹H-NMR (DMSO-D₆) δ: 0.63-0.75 (2H, m), 1.01 (6H, s), 1.03-1.14 (4H, m),1.30-1.38 (2H, m), 1.41-1.49 (2H, m), 1.50- 1.60 (5H, m), 1.98-2.05 (2H,m), 2.41 (2H, s), 2.64-2.71 (2H, m), 3.17 (3H, s), 6.57-6.64 (1H, m),6.82-6.88 (1H, m), 7.20-7.25 (1H, m), 7.52- 7.57 (1H, m), 11.39 (1H, brs), 12.54 (1H, br s). 433 431 94

¹H-NMR (DMSO-D₆) δ: 0.92-0.99 (2H, m), 1.01 (6H, s), 1.46-1.53 (2H, m),1.56-1.61 (2H, m), 1.89-1.98 (3H, m), 2.41 (2H, s), 2.64-2.70 (2H, m),3.16-3.26 (2H, m), 3.18 (3H, s), 3.69-3.75 (2H, m), 6.56-6.63 (1H, m),6.81-6.87 (1H, m), 7.18-7.24 (1H, m), 7.52- 7.58 (1H, m), 11.40 (1H, brs), 12.54 (1H, br s). 421 419 95

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.06-1.18 (1H, m), 1.31-1.49 (2H, m),1.56-1.61 (2H, m), 1.65-1.77 (2H, m), 2.42 (2H, s), 2.64-2.72 (2H, m),2.90-2.96 (1H, m), 3.05-3.13 (1H, m), 3.21 (3H, s), 3.36-3.42 (1H, m),3.62-3.69 (1H, m), 3.75-3.81 (1H, m), 4.75 (1H, d, J = 7.7 Hz),6.57-6.64 (1H, m), 6.85- 6.91 (1H, m), 7.22-7.27 (1H, m), 7.53-7.58 (1H,m), 11.43 (1H, br s), 12.53 (1H, br s). 437 435 96

¹H-NMR (DMSO-D₆) δ: 0.93-1.11 (2H, m), 1.01 (6H, s), 1.28-1.85 (5H, m),2.42 (2H, s), 2.64- 2.70 (2H, m), 2.97-3.16 (2H, m), 3.21 (3H, s),3.57-3.78 (2H, m), 4.45- 4.49 (1H, m), 4.96 (1H, d, J = 8.1 Hz),6.58-6.61 (1H, m), 6.84-6.89 (1H, m), 7.23-7.27 (1H, m), 7.52-7.57 (1H,m), 11.42 (1H, br s), 12.53 (1H, br s). 437 435

TABLE 1-20 Ex. MS MS No. structural formula NMR (M + H) (M − H) 97

¹H-NMR (DMSO-D₆) δ: 0.48-0.60 (1H, m), 0.72- 0.84 (1H, m), 0.91 (3H, d,J = 6.7 Hz), 1.01 (6H, s), 1.06-1.18 (2H, m), 1.35- 1.45 (1H, m),1.51-1.70 (8H, m), 2.05-2.14 (1H, m), 2.42 (2H, s), 2.64- 2.71 (2H, m),3.18 (3H, s), 6.58-6.63 (1H, m), 6.80-6.86 (1H, m), 7.19- 7.24 (1H, m),7.53-7.58 (1H, m), 11.37 (1H, br s), 12.53 (1H, br s). 433 431 98

¹H-NMR (DMSO-D₆) δ: 0.77-0.89 (1H, m), 0.92 (3H, d, J = 6.7 Hz), 1.01(6H, s), 1.05-1.14 (1H, m), 1.45-1.54 (2H, m), 1.56-1.69 (3H, m), 2.09-2.17 (1H, m), 2.42 (3H, s), 2.65-2.70 (2H, m), 3.14-3.25 (2H, m), 3.19(3H, s), 3.72-3.81 (2H, m), 6.57-6.62 (1H, m), 6.81-6.86 (1H, m), 7.20-7.24 (1H, m), 7.54-7.59 (1H, m), 11.38 (1H, br s), 12.54 (1H, br s). 435433 99

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.08-1.65 (10H, m), 1.76-1.84 (1H, m),2.42 (2H, s), 2.65- 2.71 (2H, m), 2.84 (3H, s), 3.15 (3H, s), 3.36-3.40(1H, m), 6.58-6.64 (1H, m), 6.84-6.89 (1H, m), 7.21-7.27 (1H, m), 7.53-7.59 (1H, m), 11.38 (1H, br s), 12.53 (1H, br s). 435 433 100

¹H-NMR (DMSO-D₆) δ: 0.80-1.08 (2H, m), 1.01 (6H, s), 1.16-1.34 (2H, m),1.51-1.66 (4H, m), 1.81-1.96 (2H, m), 2.20- 2.30 (1H, m), 2.42 (2H, s),2.65-2.77 (3H, m), 3.12 (3H, s), 3.16 (3H, s), 6.59-6.65 (1H, m), 6.85-6.92 (1H, m), 7.23-7.29 (1H, m), 7.54-7.59 (1H, m), 11.38 (1H, br s),12.54 (1H, br s). 435 433 101

¹H-NMR (DMSO-D₆) δ: 0.66-0.78 (2H, m), 1.01 (6H, s), 1.36-1.48 (2H, m),1.55-1.65 (4H, m), 1.68-1.76 (2H, m), 2.06- 2.15 (1H, m), 2.42 (2H, s),2.64-2.72 (2H, m), 3.15 (3H, s), 3.20-3.29 (1H, m), 4.36 (1H, d, J = 4.6Hz), 6.59-6.65 (1H, m), 6.83-6.90 (1H, m), 7.21-7.28 (1H, m), 7.53- 7.61(1H, m), 11.35 (1H, br s), 12.52 (1H, br s). 421 419

TABLE 1-21 Ex. MS MS No. structural formula NMR (M + H) (M − H) 102

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.15-1.45 (6H, m), 1.49-1.62 (4H, m),1.67-1.78 (2H, m), 2.41 (2H, s), 2.62-2.71 (2H, m), 3.23 (3H, s),4.57-4.64 (1H, m), 6.52- 6.57 (1H, m), 6.83-6.89 (1H, m), 7.22-7.27 (1H,m), 7.42-7.48 (1H, m), 11.26 (1H, br s), 12.49 (1H, br s). 421 419 103

¹H-NMR (DMSO-D₆) δ: 0.94-1.06 (1H, m), 1.01 (6H, s), 1.37-1.44 (2H, m),1.55-1.61 (2H, m), 1.64-1.71 (1H, m), 1.86- 1.96 (3H, m), 2.41 (2H, s),2.63-2.71 (2H, m), 2.80-2.87 (1H, m), 3.13- 3.21 (1H, m), 3.18 (3H, s),3.61-3.68 (2H, m), 6.58-6.62 (1H, m), 6.82- 6.87 (1H, m), 7.18-7.23 (1H,m), 7.52-7.57 (1H, m), 11.39 (1H, br s), 12.53 (1H, br s). 421 419 104

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.02 (3H, d, J = 7.0 Hz), 1.54-1.62(2H, m), 2.21-2.29 (2H, m), 2.38-2.49 (2H, m), 2.42 (2H, s), 2.64-2.70(2H, m), 3.15-3.24 (1H, m), 3.19 (3H, s), 3.45- 3.51 (4H, m), 6.56-6.62(1H, m), 6.85-6.93 (1H, m), 7.26-7.33 (1H, m), 7.51-7.57 (1H, m), 11.39(1H, br s), 12.54 (1H, br s). 436 434 105

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 1.64-1.73 (4H, m),2.14-2.20 (2H, m), 2.42 (2H, s), 2.64-2.73 (2H, m), 3.17-3.26 (2H, m),3.19 (3H, s), 3.77 (2H, s), 6.58-6.64 (1H, m), 6.89-6.96 (1H, m),7.27-7.33 (1H, m), 7.54- 7.61 (1H, m), 11.45 (1H, br s), 12.54 (1H, brs). 434 432 106

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.02 (3H, s), 1.40 (3H, s), 1.55- 1.61(2H, m), 2.41 (2H, s), 2.59-2.71 (3H, m), 2.78-2.86 (1H, m), 3.14- 3.19(1H, m), 3.24 (3H, s), 6.59-6.64 (1H, m), 6.88-6.93 (1H, m), 7.25- 7.29(1H, m), 7.56-7.61 (1H, m), 11.39 (1H, br s), 12.52 (1H, br s). 435 433

TABLE 1-22 Ex. MS MS No. structural formula NMR (M + H) (M − H) 107

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.22-1.39 (2H, m), 1.54-1.66 (4H, m),1.95-2.06 (2H, m), 2.42 (2H, s), 2.53-2.61 (2H, m), 2.64-2.70 (2H, m),2.82 (2H, s), 3.17 (3H, s), 3.29-3.37 (1H, m), 4.46 (1H, d, J = 3.9 Hz),6.57-6.61 (1H, m), 6.83-6.88 (1H, m), 7.22- 7.26 (1H, m), 7.50-7.56 (1H,m), 11.40 (1H, br s), 12.53 (1H, br s). 436 434 108

¹H-NMR (DMSO-D₆) δ: 1.00 (3H, d, J = 7.7 Hz), 1.01 (6H, s), 1.20-1.32(2H, m), 1.52-1.67 (4H, m), 2.01-2.10 (1H, m), 2.19-2.29 (1H, m), 2.35-2.47 (1H, m), 2.42 (2H, s), 2.57-2.64 (1H, m), 2.65-2.70 (2H, m), 3.17(3H, s), 3.18-3.25 (1H, m), 3.27-3.37 (1H, m), 4.45 (1H, d, J = 3.9 Hz),6.56-6.61 (1H, m), 6.83- 6.90 (1H, m), 7.23-7.29 (1H, m), 7.50-7.57 (1H,m), 11.39 (1H, br s), 12.53 (1H, br s). 450 448 109

¹H-NMR (DMSO-D₆) δ: 0.85-0.97 (1H, m), 1.01 (6H, s), 1.23-1.39 (2H, m),1.45-1.53 (1H, m), 1.55-1.63 (2H, m), 1.67- 1.76 (2H, m), 1.79-1.89 (1H,m), 2.42 (2H, s), 2.64-2.70 (2H, m), 2.71- 2.78 (1H, m), 2.80-2.91 (2H,m), 3.17 (3H, s), 3.28-3.43 (1H, m), 4.48 (1H, d, J = 4.9 Hz), 6.57-6.62 (1H, m), 6.83-6.90 (1H, m), 7.21-7.27 (1H, m), 7.50-7.58 (1H, m),11.40 (1H, br s), 12.53 (1H, br s). 436 434 110

¹H-NMR (DMSO-D₆) δ: 0.89-0.99 (1H, m), 1.01 (6H, s), 1.26-1.39 (1H, m),1.44-1.53 (1H, m), 1.55-1.62 (2H, m), 1.67- 1.78 (2H, m), 1.80-1.90 (1H,m), 2.42 (2H, s), 2.63-2.70 (2H, m), 2.71- 2.78 (1H, m), 2.80-2.93 (2H,m), 3.17 (3H, s), 3.33-3.44 (1H, m), 4.48 (1H, d, J = 4.6 Hz), 6.57-6.62 (1H, m), 6.82-6.90 (1H, m), 7.21-7.27 (1H, m), 7.49-7.58 (1H, m),11.40 (1H, br s), 12.53 (1H, br s). 436 434 111

¹H-NMR (DMSO-D₆) δ: 0.90-1.09 (2H, m), 1.01 (6H, s), 1.20-1.36 (2H, m),1.40-1.62 (4H, m), 1.69-2.26 (4H, m), 2.41 (2H, s), 2.57-2.79 (4H, m),3.18 (3H, s), 3.21- 3.41 (1H, m), 4.41-4.50 (1H, m), 6.55-6.63 (1H, m),6.83-6.91 (1H, m), 7.22-7.31 (1H, m), 7.51- 7.57 (1H, m), 11.38 (1H, brs), 12.53 (1H, br s). 450 448

TABLE 1-23 Ex. MS MS No. structural formula NMR (M + H) (M − H) 112

¹H-NMR (DMSO-D₆) δ: 0.90-1.09 (3H, m), 1.01 (6H, s), 1.19-2.27 (10H, m),2.42 (2H, s), 2.57- 2.80 (3H, m), 3.18 (3H, s), 3.22-3.41 (1H, m),4.40-4.51 (1H, m), 6.54- 6.63 (1H, m), 6.83-6.91 (1H, m), 7.23-7.32 (1H,m), 7.51-7.57 (1H, m), 11.38 (1H, br s), 12.53 (1H, br s). 450 448 113

¹H-NMR (DMSO-D₆) δ: 0.96-1.04 (9H, m), 1.23- 1.36 (2H, m), 1.54-1.62(2H, m), 1.67-1.78 (2H, m), 2.04-2.12 (1H, m), 2.22-2.30 (1H, m), 2.37-2.45 (1H, m), 2.42 (2H, s), 2.58-2.75 (3H, m), 3.00-3.08 (1H, m), 3.17(3H, s), 3.18 (3H, s), 3.19-3.25 (1H, m), 6.57- 6.61 (1H, m), 6.84-6.90(1H, m), 7.25-7.30 (1H, m), 7.50-7.56 (1H, m), 11.40 (1H, br s), 12.53(1H, br s). 464 462 114

¹H-NMR (DMSO-D₆) δ: 0.89-1.06 (1H, m), 1.01 (6H, s), 1.23-1.39 (1H, m),1.49-1.62 (3H, m), 1.79-1.88 (2H, m), 1.90- 2.00 (1H, m), 2.42 (2H, s),2.47-2.55 (1H, m), 2.63-2.69 (2H, m), 2.75- 2.82 (1H, m), 2.85-2.94 (2H,m), 3.05-3.14 (1H, m), 3.15-3.21 (6H, m), 6.56-6.62 (1H, m), 6.83- 6.90(1H, m), 7.21-7.27 (1H, m), 7.50-7.58 (1H, m), 11.41 (1H, br s), 12.53(1H, br s). 450 448 115

¹H-NMR (DMSO-D₆) δ: 0.90-0.99 (1H, m), 1.01 (6H, s), 1.23-1.40 (1H, m),1.48-1.62 (3H, m), 1.78-1.88 (2H, m), 1.90- 2.00 (1H, m), 2.42 (2H, s),2.48-2.55 (1H, m), 2.63-2.70 (2H, m), 2.75- 2.82 (1H, m), 2.84-2.94 (2H,m), 3.04-3.14 (1H, m), 3.15-3.21 (6H, m), 6.56-6.62 (1H, m), 6.83- 6.90(1H, m), 7.21-7.28 (1H, m), 7.49-7.58 (1H, m), 11.41 (1H, br s), 12.53(1H, br s). 450 448 116

¹H-NMR (DMSO-D₆) δ: 0.90-1.11 (10H, m), 1.20-1.65 (4H, m), 1.80- 2.34(4H, m), 2.42 (2H, s), 2.47-2.59 (1H, m), 2.63-2.75 (2H, m), 2.83- 3.05(1H, m), 3.06-3.30 (7H, m), 6.56-6.63 (1H, m), 6.84-6.91 (1H, m),7.24-7.31 (1H, m), 7.51- 7.58 (1H, m), 11.40 (1H, br s), 12.53 (1H, brs). 464 462

TABLE 1-24 Ex. MS MS No. structural formula NMR (M + H) (M − H) 117

¹H-NMR (DMSO-D₆) δ: 0.90-1.08 (10H, m), 1.19-1.64 (4H, m), 1.80- 2.05(3H, m), 2.11-2.35 (1H, m), 2.42 (2H, s), 2.48-2.57 (1H, m), 2.63- 2.75(2H, m), 2.83-3.30 (8H, m), 6.57-6.62 (1H, m), 6.85-6.94 (1H, m),7.24-7.31 (1H, m), 7.51- 7.58 (1H, m), 11.40 (1H, br s), 12.53 (1H, brs). 464 462 118

¹H-NMR (DMSO-D₆) δ: 0.92-1.09 (12H, m), 1.55-1.60 (2H, m), 1.61- 2.37(2H, m), 2.41 (2H, s), 2.56-2.88 (6H, m), 3.18 (3H, s), 3.44-3.84 (2H,m), 6.55-6.63 (1H, m), 6.83-6.91 (1H, m), 7.22-7.30 (1H, m), 7.50- 7.56(1H, m), 11.41(1H, br s), 12.54 (1H, br s). 450 448 119

¹H-NMR (DMSO-D₆) δ: 0.96 (6H, d, J = 6.3 Hz), 1.01 (6H, s), 1.56-1.60(2H, m), 1.62-1.69 (2H, m), 2.42 (2H, s), 2.57- 2.63 (2H, m), 2.65-2.71(2H, m), 2.84 (2H, s), 3.18 (3H, s), 3.44-3.55 (2H, m), 6.57-6.63 (1H,m), 6.84-6.90 (1H, m), 7.23-7.28 (1H, m), 7.50- 7.57 (1H, m), 11.42 (1H,br s), 12.54 (1H, br s). 450 448 120

¹H-NMR (DMSO-D₆) δ: 0.90-1.12 (15H, m), 1.54-1.62 (2H, m), 1.76- 2.03(2H, m), 2.28-2.56 (4H, m), 2.64-2.70 (2H, m), 3.15-3.24 (4H, m),3.40-3.84 (2H, m), 6.57- 6.63 (1H, m), 6.84-6.91 (1H, m), 7.25-7.30 (1H,m), 7.51-7.58 (1H, m), 11.42 (1H, br s), 12.54 (1H, br s). 464 462 121

¹H-NMR (DMSO-D₆) δ: 0.92-1.13 (15H, m), 1.55-1.61 (2H, m), 1.76- 2.02(2H, m), 2.29-2.56 (4H, m), 2.63-2.70 (2H, m), 3.16-3.24 (4H, m),3.38-3.51 (2H, m), 6.57- 6.62 (1H, m), 6.84-6.90 (1H, m), 7.25-7.30 (1H,m), 7.52-7.56 (1H, m), 11.42 (1H, br s), 12.54 (1H, br s). 464 462

TABLE 1-25 Ex. MS MS No. structural formula NMR (M + H) (M − H) 122

¹H-NMR (DMSO-D₆) δ: 0.97-1.04 (9H, m), 1.26- 1.34 (2H, m), 1.35-1.43(4H, m), 1.53-1.62 (2H, m), 2.18-2.27 (2H, m), 2.37-2.45 (2H, m), 2.42(2H, s), 2.64-2.70 (2H, m), 3.18 (3H, s), 3.19-3.23 (1H, m), 6.57-6.62(1H, m), 6.84-6.91 (1H, m), 7.24-7.30 (1H, m), 7.50- 7.56 (1H, m), 11.37(1H, br s), 12.53 (1H, br s). 434 432 123

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.26-1.38 (2H, m), 1.53-1.65 (3H, m),1.76-1.86 (1H, m), 2.42 (2H, s), 2.63-2.72 (2H, m), 3.03-3.14 (1H, m),3.19 (3H, s), 3.21- 3.30 (2H, m), 3.50-3.57 (1H, m), 3.60-3.67 (1H, m),3.77-3.88 (2H, m), 6.57-6.65 (1H, m), 6.85- 6.93 (1H, m), 7.23-7.30 (1H,m), 7.51-7.57 (1H, m), 11.42 (1H, br s), 12.54 (1H, br s). 437 435 124

¹H-NMR (DMSO-D₆) δ: 0.78-0.91 (1H, m), 1.01 (6H, s), 1.05-1.51 (6H, m),1.52-1.69 (4H, m), 1.76- 1.83 (1H, m), 2.14-2.26 (1H, m), 2.42 (2H, s),2.64-2.71 (2H, m), 3.15 (3H, s), 6.59-6.63 (1H, m), 6.83-6.89 (1H, m),7.22- 7.26 (1H, m), 7.53-7.58 (1H, m), 11.34 (1H, br s), 12.19 (1H, brs). 405 403 125

¹H-NMR (DMSO-D₆) δ: 0.89-0.97 (3H, m), 1.01 (6H, s), 1.56-1.61 (2H, m),2.06-2.31 (2H, m), 2.41 (2H, s), 2.65-2.70 (2H, m), 2.72-2.94 (3H, m),3.16- 3.25 (3H, m), 3.78-3.84 (2H, m), 6.59-6.64 (1H, m), 6.89-6.98 (1H,m), 7.28-7.34 (1H, m), 7.54- 7.61 (1H, m), 11.42 (1H, br s), 12.51 (1H,br s). 422 420 126

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 1.80 (1H, br s),2.13-2.18 (3H, m), 2.41 (2H, s), 2.64-2.70 (2H, m), 2.92-2.97 (2H, m),3.21 (3H, s), 6.58-6.63 (1H, m), 6.84-6.89 (1H, m), 7.22- 7.26 (1H, m),7.53-7.58 (1H, m), 11.37 (1H, br s), 12.51 (1H, br s). 366 364

TABLE 1-26 Ex. MS MS No. structural formula NMR (M + H) (M − H) 127

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.46-1.69 (8H, m), 2.34-2.45 (2H, m),2.42 (2H, s), 2.64- 2.72 (2H, m), 3.18 (3H, s), 3.29-3.36 (2H, m), 3.82(2H, s), 6.58-6.65 (1H, m), 6.90-6.96 (1H, m), 7.27- 7.35 (1H, m),7.54-7.60 (1H, m), 11.44 (1H, br s), 12.54 (1H, br s). 448 446 128

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 1.81-2.02 (3H, m),2.08-2.18 (1H, m), 2.41 (2H, s), 2.64-2.70 (2H, m), 3.21 (3H, s),4.00-4.04 (1H, m), 6.59- 6.63 (1H, m), 6.88-6.93 (1H, m), 7.27-7.30 (1H,m), 7.55-7.59 (1H, m), 7.63 (1H, br s), 11.45 (1H, br s), 12.55 (1H, brs). 406 404 129

¹H-NMR (DMSO-D₆) δ: 0.84-0.92 (3H, m), 1.01 (6H, s), 1.54-1.61 (2H, m),1.72-1.85 (2H, m), 2.42 (2H, s), 2.64-2.71 (2H, m), 3.01-3.52 (5H, m),3.32 (3H, s), 3.72-3.98 (5H, m), 6.63-6.67 (1H, m), 6.95- 7.01 (1H, m),7.33-7.37 (1H, m), 7.61-7.65 (1H, m), 10.25 (1H, br s), 11.49 (1H, brs). 450 448 130

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.08 (3H, d, J = 6.6 Hz), 1.55-1.61(2H, m), 2.42 (2H, s), 2.64-2.71 (2H, m), 3.20 (3H, s), 3.47-3.55 (2H,m), 3.56-3.61 (1H, m), 3.76- 3.81 (1H, m), 3.98 (1H, d, J = 16.5 Hz),4.03 (1H, d, J = 16.8 Hz), 4.08-4.15 (1H, m), 6.59-6.64 (1H, m),6.93-6.99 (1H, m), 7.31-7.36 (1H, m), 7.55- 7.61 (1H, m), 11.46 (1H, brs), 12.54 (1H, br s). 450 448 131

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.32-1.63 (10H, m), 2.42 (2H, s),2.62-2.73 (2H, m), 3.13- 3.19 (1H, m), 3.20 (3H, s), 3.37-3.44 (1H, m),3.64- 3.70 (1H, m), 4.04-4.12 (1H, m), 4.92 (1H, d, J = 7.4 Hz),6.56-6.64 (1H, m), 6.84-6.94 (1H, m), 7.23-7.31 (1H, m), 7.50- 7.59 (1H,m), 11.46 (1H, br s), 12.54 (1H, br s). 451 449

TABLE 1-27 Ex. MS MS No. structural formula NMR (M + H) (M − H) 132

¹H-NMR (DMSO-D₆) δ: 0.94-0.98 (6H, m), 1.01 (6H, s), 1.54-1.61 (2H, m),2.41 (2H, s), 2.63- 2.71 (2H, m), 3.14-3.19 (1H, m), 3.20 (3H, s),3.34-3.40 (1H, m), 3.41- 3.47 (1H, m), 4.03-4.11 (1H, m), 4.90 (1H, d,.J = 6.6 Hz), 6.56-6.63 (1H, m), 6.85-6.92 (1H, m), 7.24-7.31 (1H, m),7.51- 7.57 (1H, m), 11.45 (1H, br s), 12.53 (1H, br s). 425 423 133

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.06 (3H, d, J = 7.0 Hz), 1.39-1.73(6H, m), 1.85-2.05 (2H, m), 2.41 (2H, s), 2.61- 2.73 (2H, m), 2.88-2.96(1H, m), 3.16 (3H, s), 3.19-3.27 (1H, m), 4.82- 4.93 (1H, m), 6.53-6.62(1H, m), 6.86-6.95 (1H, m), 7.23-7.34 (1H, m), 7.47-7.54 (1H, m), 11.37(1H, br s), 12.53 (1H, br s). 448 446 134

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.09 (3H, d, J = 7.1 Hz), 1.55-1.61(2H, m), 1.76-1.97 (2H, m), 2.04-2.11 (2H, m), 2.41 (2H, s), 2.64-2.71(2H, m), 3.17 (3H, s), 3.21-3.28 (1H, m), 3.49- 3.56 (1H, m), 4.58-4.66(1H, m), 6.56-6.63 (1H, m), 6.88-6.94 (1H, m), 7.25-7.31 (1H, m), 7.51-7.57 (1H, m), 11.39 (1H, br s), 12.53 (1H, br s). 434 432 135

¹H-NMR (DMSO-D₆) δ: 0.99-1.04 (9H, m), 1.55- 1.60 (2H, m), 2.21-2.29(2H, m), 2.38-2.48 (2H, m), 2.41 (2H, s), 2.63- 2.69 (2H, m), 3.16-3.23(1H, m), 3.19 (3H, s), 3.45-3.50 (4H, m), 6.58- 6.60 (1H, m), 6.86-6.90(1H, m), 7.27-7.30 (1H, m), 7.52-7.56 (1H, m), 11.39 (1H, br s), 12.53(1H, br s). 436 434 136

¹H-NMR (DMSO-D₆) δ: 0.99-1.07 (3H, m), 1.01 (6H, s), 1.39-1.50 (1H, m),1.55-1.61 (2H, m), 2.08-2.24 (3H, m), 2.40- 2.44 (2H, m), 2.65-2.71 (2H,m), 3.19 (3H, s), 3.40 (1H, d, J = 16.9 Hz), 3.68-3.76 (1H, m), 3.94(1H, d, J = 16.9 Hz), 6.59-6.63 (1H, m), 6.92- 6.98 (1H, m), 7.30-7.35(1H, m), 7.56-7.61 (1H, m), 11.41 (1H, br s), 12.51 (1H, br s). 434 432

TABLE 1-28 Ex. MS MS No. structural formula NMR (M + H) (M − H) 137

¹H-NMR (DMSO-D₆) δ: 0.96-1.08 (3H, m), 1.01 (6H, s), 1.46-1.65 (4H, m),1.71-1.90 (2H, m), 2.14-2.19 (2H, m), 2.41 (2H, s), 2.64-2.71 (2H, m),3.19 (3H, s), 3.42- 3.52 (2H, m), 4.04-4.11 (1H, m), 6.58-6.62 (1H, m),6.91-6.97 (1H, m), 7.30-7.34 (1H, m), 7.54- 7.59 (1H, m), 11.40 (1H, brs), 12.51 (1H, br s). 448 446 138

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 2.18-2.25 (2H, m),2.42 (2H, s), 2.65- 2.71 (2H, m), 3.09-3.14 (2H, m), 3.20 (3H, s),3.29-3.34 (2H, m), 3.51 (2H, s), 6.58-6.64 (1H, m), 6.88-6.94 (1H, m),7.26-7.31 (1H, m), 7.55- 7.60 (1H, m), 11.43(1H, br s), 12.51 (1H, brs). 456 454 139

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.79 (4H, m), 1.84-1.95 (2H, m),2.41 (2H, s), 2.64- 2.70 (2H, m), 3.19 (3H, s), 3.59-3.66 (1H, m),3.78-3.85 (1H, m), 4.16- 4.23 (1H, m), 6.57-6.65 (1H, m), 6.85-6.92 (1H,m), 7.23-7.31 (1H, m), 7.52-7.58 (1H, m), 11.41 (1H, br s), 12.53 (1H,br s). 393 391 140

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.78 (4H, m), 1.84-1.95 (2H, m),2.41 (2H, s), 2.62.- 2.72 (2H, m), 3.18 (3H, s), 3.58-3.66 (1H, m),3.78-3.85 (1H, m), 4.16- 4.22 (1H, m), 6.56-6.64 (1H, m), 6.84-6.93 (1H,m), 7.21-7.29 (1H, m), 7.52-7.59 (1H, m), 11.41 (1H, br s), 12.53 (1H,br s). 393 391 141

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.64 (6H, m), 2.05-2.11 (2H, m),2.19-2.26 (2H, m), 2.42 (2H, s), 2.63-2.69 (2H, m), 3.10-3.15 (2H, m),3.18 (3H, s), 3.34- 3.40 (2H, m), 6.57-6.61 (1H, m), 6.83-6.88 (1H, m),7.20-7.23 (1H, m), 7.52-7.56 (1H, m), 11.42 (1H, br s), 12.53 (1H, brs). 448 446

TABLE 1-29 Ex. MS MS No. structural formula NMR (M + H) (M − H) 142

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.63 (3H, m), 2.04-2.14 (4H, m),2.41 (2H, s), 2.44- 2.53 (4H, m), 2.64-2.70 (2H, m), 3.21 (3H, s),3.79-3.87 (1H, m), 6.57- 6.62 (1H, m), 6.86-6.92 (1H, m), 7.23-7.28 (1H,m), 7.53-7.58 (1H, m), 11.37 (1H, br s), 12.51 (1H, br s). 434 432 143

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.46-1.54 (1H, m), 1.55-1.61 (2H, m),1.91-2.19 (4H, m), 2.24-2.31 (1H, m), 2.41 (2H, s), 2.64-2.70 (2H, m),3.19 (3H, s), 3.78- 3.86 (1H, m), 6.58-6.63 (1H, m), 6.86-6.91 (1H, m),7.22-7.28 (1H, m), 7.35 (1H, br s), 7.53- 7.58 (1H, m), 11.41 (1H, brs), 12.53 (1H, br s). 420 418 144

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 1.77-1.86 (2H, m),2.07-2.13 (2H, m), 2.18-2.23 (2H, m), 2.41 (2H, s), 2.64-2.70 (2H, m),3.15-3.21 (2H, m), 3.18 (3H, s), 3.29-3.35 (2H, m), 6.57-6.62 (1H, m),6.84-6.89 (1H, m), 7.20-7.25 (1H, m), 7.52- 7.57 (1H, m), 11.38 (1H, brs), 12.51 (1H, br s). 434 432 145

¹H-NMR (DMSO-D₆) δ: 0.59 (3H, d, J = 6.0 Hz), 1.01 (6H, s), 1.51-1.62(2H m) 2.31-2.49 (2H, m), 2.41 (2H, s), 2.56- 2.74 (3H, m), 2.82-2.95(2H, m), 3.14-3.23 (1H, m), 3.18 (3H, s), 3.33- 3.41 (1H, m), 3.43-3.50(1H, m), 3.55-3.63 (1H, m), 6.55-6.64 (1H, m), 6.82-6.92 (1H, m), 7.22-7.30 (1H, m), 7.49-7.58 (1H, m), 11.39 (1H, br s), 12.53 (1H, br s). 436434 146

¹H-NMR (DMSO-D₆) δ: −0.12-1.17 (6H, m), 1.01 (6H, s), 1.54-1.62 (2H, m),2.19-2.48 (2H, m), 2.41 (2H, s), 2.60-2.92 (4H, m), 3.12-3.80 (4H, m),3.17 (3H, s), 6.50- 6.62 (1H, m), 6.84-6.99 (1H, m), 7.26-7.42 (1H, m),7.48-7.58 (1H, m), 11.37-11.44 (1H, m), 12.53 (1H, br s). 450 448

TABLE 1-30 Ex. MS MS No. structural formula NMR (M + H) (M − H) 147

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.10 (3H, d, J = 7.0 Hz), 1.53-1.62(2H, m), 2.42 (2H, s), 2.62-2.76 (2H, m), 3.11- 3.22 (1H, m), 3.18 (3H,s), 3.39-3.47 (1H, m), 3.64- 3.73 (1H, m), 3.75-3.92 (3H, m), 4.91-5.00(1H, m), 6.55-6.60 (1H, m), 6.91-6.97 (1H, m), 7.28- 7.33 (1H, m),7.50-7.56 (1H, m), 11.43 (1H, br s), 12.53 (1H, br s). 450 448 148

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.47-1.76 (6H, m), 1.96-2.04 (1H, m),2.12 (3H, s), 2.41 (2H, s), 2.63-2.69 (2H, m), 2.83-2.91 (2H, m), 3.19(3H, s), 6.58-6.62 (1H, m), 6.81-6.86 (1H, m), 7.19- 7.23 (1H, m),7.52-7.57 (1H, m), 11.37 (1H, br s), 12.53 (1H, br s). 406 404 149

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.47-1.76 (6H, m), 1.96-2.05 (1H, m),2.12 (3H, s), 2.41 (2H, s), 2.63-2.70 (2H, m), 2.84-2.92 (2H, m), 3.19(3H, s), 6.57-6.63 (1H, m), 6.80-6.87 (1H, m), 7.18- 7.24 (1H, m),7.52-7.58 (1H, m), 11.37 (1H, br s), 12.53 (1H, br s). 406 404 150

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 1.79-1.94 (2H, m),2.03-2.12 (1H, m), 2.19-2.29 (1H, m), 2.42 (2H, s), 2.57 (3H, s), 2.64-2.71 (2H, m), 3.24 (3H, s), 4.04-4.08 (1H, m), 6.60- 6.63 (1H, m),6.92-6.97 (1H, m), 7.29-7.32 (1H, m), 7.57-7.62 (1H, m), 11.44 (1H, brs), 12.54 (1H, br s). 420 418 151

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 1.80-1.93 (2H, m),2.03-2.12 (1H, m), 2.19-2.29 (1H, m), 2.42 (2H, s), 2.57 (3H, s), 2.64-2.71 (2H, m), 3.24 (3H, s), 4.03-4.08 (1H, m), 6.60- 6.63 (1H, m),6.91-6.97 (1H, m), 7.29-7.32 (1H, m), 7.57-7.61 (1H, m), 11.44 (1H, brs), 12.54 (1H, br s). 420 418

TABLE 1-31 Ex. MS MS No. structural formula NMR (M + H) (M − H) 152

  stereoisomer of Ex. No. 153 ¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s),1.15-1.25 (6H, m), 1.55-1.60 (2H, m), 2.41 (2H, s), 2.64- 2.71 (2H, m),2.88-2.99 (1H, m), 3.12-3.21 (1H, m), 3.16 (3H, s), 3.36- 3.42 (1H, m),3.82-3.88 (1H, m), 3.93-4.00 (1H, m), 4.47-4.55 (1H, m), 6.56-6.60 (1H,m), 6.90- 6.95 (1H, m), 7.28-7.31 (1H, m), 7.50-7.55 (1H, m), 11.39 (1H,br s), 12.53 (1H, br s). 464 462 153

  stereoisomer of Ex. No. 152 ¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s),1.15-1.26 (6H, m), 1.55-1.61 (2H, m), 2.41 (2H, s), 2.63- 2.71 (2H, m),3.19 (3H, s), 3.64-3.73 (2H, m), 3.79- 3.89 (2H, m), 3.93-4.01 (1H, m),4.90-4.98 (1H, m), 6.56-6.60 (1H, m), 6.91-6.97 (1H, m), 7.28- 7.32 (1H,m), 7.50-7.55 (1H, m), 11.45 (1H, br s), 12.53 (1H, br s). 464 462 154

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 2.42 (2H, s),2.65-2.70 (2H, m), 3.21 (3H, s), 3.54-3.60 (2H, m), 3.69 (2H, s),4.21-4.28 (2H, m), 6.60-6.63 (1H, m), 6.91-6.95 (1H, m), 422 4207.29-7.31 (1H, m), 7.57- 7.61 (1H, m), 11.47 (1H, br s), 12.54 (1H, brs). 155

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 2.39-2.46 (2H, m),2.41 (2H, s), 2.64- 2.71 (2H, m), 2.89-2.96 (2H, m), 3.00-3.04 (2H, m),3.16 (3H, s), 3.21 (6H, s), 3.70-3.76 (2H, m), 6.57-6.62 (1H, m), 6.83-6.89 (1H, m), 7.20-7.26 (1H, m), 7.51-7.56 (1H, 466 464 m), 11.40 (1H,br s), 12.53 (1H, br s). 156

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.53-1.62 (2H, m), 2.42 (2H, s),2.63-2.72 (2H, m), 3.22 (3H, s), 4.43 (2H, s), 6.12- 6.20 (1H, m),6.28-6.35 (1H, m), 6.60-6.67 (1H, m), 6.99-7.05 (1H, m), 7.35-7.46 (2H,m), 7.51- 7.57 (1H, m), 7.59-7.65 (1H, m), 11.50 (1H, br s), 12.55 (1H,br s). 430 428

TABLE 1-32 Ex. MS MS No. structural formula NMR (M + H) (M − H) 157

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 2.42 (2H, s),2.65-2.71 (2H, m), 3.23 (3H, s), 4.71 (2H, s), 6.18-6.22 (1H, m),6.62-6.66 (1H, m), 6.98-7.03 (1H, m), 7.34-7.41 (2H, m), 7.59-7.64 (2H,m), 11.48 (1H, br s), 12.55 (1H, br s). 403 401 158

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.19-1.29 (1H, m), 1.32-1.69 (9H, m),2.42 (2H, s), 2.62-2.74 (2H, m), 3.20 (3H, s), 3.29-3.38 (1H, m),3.45-3.52 (1H, m), 3.74-3.84 (1H, m), 3.89-3.96 (1H, m), 4.63 (1H, brs), 6.60-6.64 (1H, m), 6.87-6.93 (1H, m), 7.27-7.31 (1H, m), 7.54-7.59(1H, m), 11.42 (1H, br s), 12.54 (1H, br s). 451 449 159

¹H-NMR (DMSO-D₆) δ: 0.85 (3H, d, J = 6.0 Hz), 0.97 (3H, d, J = 6.2 Hz),1.01 (6H, s), 1.54-1.61 (2H, m), 2.41 (2H, s), 2.63-2.71 (2H, m), 3.20(3H, s), 3.30-3.38 (1H, m), 3.40-3.54 (2H, m), 3.95-4.00 (1H, m), 4.63(1H, br s), 6.58- 6.64 (1H, m), 6.87- 6.92 (1H, m), 7.26- 7.32 (1H, m),7.54- 7.59 (1H, m), 11.41 (1H, br s), 12.53 (1H, br s). 425 423 160

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 1.68-1.78 (1H, m),1.92-2.02 (1H, m), 2.08-2.27 (2H, m), 2.42 (2H, s), 2.64-2.72 (2H, m),3.20 (3H, s), 3.24-3.30 (1H, m), 3.45-3.51 (1H, m), 3.57-3.67 (2H, m),3.90-3.97 (1H, m), 4.72-4.77 (1H, m), 6.59-6.63 (1H, m), 6.91-6.96 (1H,m), 7.29-7.34 (1H, m), 7.56-7.61 (1H, m), 11.47 (1H, br s), 12.54 (1H,br s). 450 448 161

¹H-NMR (DMSO-D₆) δ: 0.92-1.38 (6H, m), 1.01 (6H, s), 1.56-1.61 (2H, m),2.23-2.60 (4H, m), 2.41 (2H, s), 2.63-2.70 (2H, m), 3.23-3.83 (7H, m),6.53-6.59 (1H, m), 6.69-6.89 (1H, m), 7.10-7.39 (1H, m), 7.43-7.48 (1H,m), 11.34 (1H, br s), 12.49 (1H, br s). 450 448

TABLE 1-33 Ex. MS MS No. structural formula NMR (M + H) (M − H) 162

¹H-NMR (DMSO-D₆) δ: 0.98-1.05 (3H, m), 1.01 (6H, s), 1.44-1.54 (1H, m),1.56-1.61 (2H, m), 2.10- 2.19 (1H, m), 2.26-2.34 (1H, m), 2.42 (2H, s),2.64-2.71 (2H, m), 3.19 (3H, s), 3.26-3.34 (2H, m), 3.65-3.76 (2H, m),6.60- 6.63 (1H, m), 6.90-6.95 (1H, m), 7.28-7.32 (1H, m), 7.56-7.60 (1H,m), 11.46 (1H, br s), 12.54 (1H, br s). 434 432 163

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.07 (6H, s), 1.55-1.61 (2H, m), 2.03(2H, s), 2.42 (2H, s), 2.64- 2.70 (2H, m), 3.09 (2H, s), 3.19 (3H, s),3.70 (2H, s), 6.59-6.63 (1H, m), 6.89- 6.95 (1H, m), 7.27-7.31 (1H, m),7.55-7.60 (1H, m), 11.46 (1H, br s), 12.54 (1H, br s). _ 448 446 164

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 1.99-2.07 (1H, m),2.38-2.48 (1H, m), 2.42 (2H, s), 2.64-2.72 (2H, m), 3.12-3.22 (1H, m),3.19 (3H, s), 3.56- 3.65 (2H, m), 3.81-3.88 (1H, m), 4.23-4.30 (1H, m),5.11 (1H, d, J = 4.4 Hz), 6.58-6.63 (1H, m), 6.90-6.96 (1H, m), 7.27-7.32 (1H, m), 7.55-7.61 (1H, m), 11.46 (1H, br s), 12.54 (1H, br s). 436434 165

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.60 (2H, m), 1.68-2.00 (7H, m),2.41 (2H, s), 2.63- 2.70 (2H, m), 3.14-3.25 (3H, m), 3.32-3.52 (2H, m),4.22-4.28 (1H, m), 6.57-6.63 (1H, m), 6.92- 6.99 (1H, m), 7.30-7.37 (1H,m), 7.52-7.61 (1H, m), 11.39-11.44 (1H, m), 12.50-12.56 (1H, m). 434 432166

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 1.62-2.01 (7H, m),2.41 (2H, s), 2.61- 2.73 (2H, m), 3.12-3.25 (3H, m), 3.36-3.55 (2H, m),4.22-4.30 (1H, m), 6.57-6.66 (1H, m), 6.92- 7.00 (1H, m), 7.31-7.43 (1H,m), 7.51-7.62 (1H, m), 11.39 (1H, br s), 12.53 (1H, br s). 434 432

TABLE 1-34 Ex. MS MS No. structural formula NMR (M + H) (M − H) 167

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.24 (3H, d, J = 6.8 Hz), 1.55-1.61(2H, m), 2.42 (2H, s), 2.64-2.70 (2H, m), 3.17- 3.24 (1H, m), 3.20 (3H,s), 3.46-3.54 (1H, m), 3.65-3.72 (1H, m), 3.73- 3.80 (1H, m), 3.82-3.91(2H, m), 4.09 (1H, q, J = 6.9 Hz), 6.59-6.63 (1H, m), 6.90-6.96 (1H, m),7.29-7.32 (1H, m), 7.55- 7.60 (1H, m), 11.47 (1H, br s), 12.54 (1H, brs). 450 448 168

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.08 (3H, d, J = 6.6 Hz), 1.55-1.60(2H, m), 2.41 (2H, s), 2.64-2.70 (2H, m), 3.04 (3H, s), 3.21 (3H, s),3.79 (1H, q, J = 6.3 Hz), 6.58-6.64 (1H, m), 6.87- 6.91 (1H, m),7.21-7.29 (1H, m), 7.54-7.59 (1H, m), 11.39 (1H, br s), 12.53 (1H, brs). 381 379 169

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.08 (3H, d, J = 6.4 Hz), 1.55-1.61(2H, m), 2.41 (2H, s), 2.64-2.71 (2H, m), 3.04 (3H, s), 3.21 (3H, s),3.79 (1H, q, J = 6.2 Hz), 6.59-6.63 (1H, m), 6.86- 6.91 (1H, m),7.23-7.29 (1H, m), 7.54-7.59 (1H, m), 11.35 (1H, br s), 12.51 (1H, brs). 381 379 170

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.66 (3H, m), 1.82-1.91 (1H, m),2.03-2.11 (1H, m), 2.36-2.44 (1H, m), 2.41 (2H, s), 2.65-2.71 (2H, m),3.14-3.23 (1H, m), 3.19 (3H, s), 3.25-3.35 (1H, m), 3.60-3.68 (1H, m),3.86-3.95 (2H, m), 4.87 (1H, d, J = 4.0 Hz), 6.59-6.64 (1H, m), 6.89-6.95 (1H, m), 7.28-7.34 (1H, m), 7.53-7.60 (1H, m), 11.40 (1H, br s),12.51 (1H, br s). 450 448 171

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.08 (3H, d, J = 6.3 Hz), 1.54-1.62(2H, m), 2.42 (2H, s), 2.62-2.75 (2H, m), 3.20 (3H, s), 3.47-3.63 (3H,m), 3.75-3.82 (1H, m), 3.98 (1H, d, J = 16.5 Hz), 4.03 (1H, d, J = 16.5Hz), 4.08-4.16 (1H, m), 6.58-6.65 (1H, m), 6.93-7.01 (1H, m), 7.30- 7.37(1H, m), 7.55-7.62 (1H, m), 11.47 (1H, br s), 12.54 (1H, br s). 450 448

TABLE 1-35 Ex. MS MS No. structural formula NMR (M + H) (M − H) 172

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.08 (3H, d, J = 6.3 Hz), 1.54-1.62(2H, m), 2.42 (2H, s), 2.63-2.71 (2H, m), 3.20 (3H, s), 3.47-3.62 (3H,m), 3.75-3.82 (1H, m), 3.98 (1H, d, J = 16.5 Hz), 4.03 (1H, d, J = 16.5Hz), 4.08-4.16 (1H, m), 6.57- 6.65 (1H, m), 6.92-7.01 (1H, m), 7.30-7.36(1H, m), 7.55-7.62 (1H, m), 11.47 (1H, br s), 12.54 (1H, br s). 450 448173

¹H-NMR (DMSO-D₆) δ: 0.78 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6.4 Hz),1.01 (6H, s), 1.55-1.61 (2H, m), 1.99-2.09 (1H, m), 2.30-2.38 (2H, m),2.41 (2H, s), 2.51-2.56 (2H, m), 2.63-2.71 (2H, m), 2.82-2.88 (1H, m),3.23 (3H, s), 3.41-3.50 (4H, m), 6.57-6.61 (1H, m), 6.82-6.88 (1H, m),7.23-7.27 (1H, m), 7.51- 7.56 (1H, m), 11.36 (1H, br s). 12.51 (1H, brs). 464 462 174

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.05 (6H, s), 1.55-1.63 (4H, m), 1.69-1.76 (2H, m), 2.41 (2H, s), 2.64-2.70 (2H, m), 3.19 (3H, s), 3.22-3.27(2H, m), 3.71 (2H, s), 6.58-6.63 (1H, m), 6.88- 6.94 (1H, m), 7.28-7.32(1H, m), 7.54-7.59 (1H, m), 11.41 (1H, br s), 12.51 (1H, br s). 462 460175

¹H-NMR (DMSO-D₆) δ: 0.96 (6H, s), 1.01 (6H, s), 1.48-1.54 (2H, m), 1.55-1.61 (2H, m), 2.16-2.22 (2H, m), 2.41 (2H, s), 2.64-2.71 (2H, m), 2.98(2H, s), 3.19 (3H, s), 3.75 (2H, s), 6.58-6.63 (1H, m), 6.88-6.95 (1H,m), 7.27-7.32 (1H, m), 7.53- 7.59 (1H, m), 11.41 (1H, br s), 12.51 (1H,br s). 462 460 176

¹H-NMR (DMSO-D₆) δ: 0.68-1.94 (11H, m), 1.01 (6H, s), 2.41 (2H, s),2.64-2.71 (2H, m), 2.88- 3.29 (9H, m), 6.56-6.63 (1H, m), 6.78-6.86 (1H,m), 7.16-7.23 (1H, m), 7.50-7.57 (1H, m), 11.35 (1H, br s), 12.50 (1H,br s). 449 447

TABLE 1-36 Ex. MS MS No. structural formula NMR (M + H) (M − H) 177

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.62 (2H, m), 1.69-1.79 (1H, m),1.92-2.03 (1H, m), 2.08-2.28 (2H, m), 2.42 (2H, s), 2.64-2.74 (2H, m),3.20 (3H, s), 3.24- 3.33 (1H, m), 3.45-3.52 (1H, m), 3.57-3.67 (2H, m),3.89-3.98 (1H, m), 4.70-4.75 (1H, m), 6.59- 6.63 (1H, m), 6.91-6.97 (1H,m), 7.30-7.34 (1H, m), 7.55-7.61 (1H, m), 11.43 (1H, br s), 12.51 (1H,br s). 450 448 178

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.56-1.61 (2H, m), 2.42 (2H, s),2.64-2.71 (2H, m), 2.82- 2.89 (3H, m), 3.17-3.22 (3H, m), 3.75 (2H, s),5.00-5.06 (2H, m), 6.57- 6.62 (1H, m), 6.70-6.94 (1H, m), 7.23-7.42 (6H,500 498 m), 7.48-7.59 (1H, m), 11.41 (1H, br s), 12.51 (1H, br s). 179

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.15 (9H, s), 1.55-1.60 (2H, m), 2.41(2H, s), 2.65-2.70 (2H, m), 3.01 (3H, s), 3.19 (3H, s), 3.77 (2H, s),6.58-6.64 (1H, m), 6.89-6.95 (1H, m), 7.29- 7.34 (1H, m), 7.54-7.60 450448 (1H, m), 11.41 (1H, br s), 12.50 (1H. br s). 180

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.60 (2H, m), 2.41 (2H, s),2.65-2.70 (2H, m), 2.73- 2.90 (3H, m), 3.18-3.27 (6H, m), 3.77-4.07 (4H,m), 6.59-6.64 (1H, m), 6.91-6.97 (1H, m), 7.30- 7.35 (1H, m), 7.55-7.60438 436 (1H, m), 11.42 (1H, br s), 12.51 (1H, br s). 181

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.14 (3H, d, J = 6.4 Hz), 1.55-1.61(2H, m), 2.42 (2H, s), 2.65-2.70 (2H, m), 3.14- 3.26 (2H, m), 3.20 (3H,s), 3.71-3.94 (3H, m), 4.02 (2H, s), 6.60-6.61 (1H, m), 6.89-6.95 (1H,m), 7.29-7.32 (1H, m), 7.55-7.60 (1H, m), 11.43 (1H, br s), 12.51 (1H,br s). 478 476

TABLE 1-37 Ex. MS MS No. structural formula NMR (M + H) (M − H) 182

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.14 (3H, d, J = 6.3 Hz), 1.55-1.61(2H, m), 2.38-2.44 (2H, m), 2.64-2.71 (2H, m), 3.15-3.26 (2H, m), 3.20(3H, s), 3.71-3.78 (1H, m), 3.80-3.95 (2H, m), 4.02 (2H, s), 6.60-6.63(1H, m), 6.91-6.95 (1H, m), 7.29- 7.32 (1H, m), 7.56-7.60 (1H, m), 11.48(1H, br s), 12.55 (1H, br s). 450 448 183

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.01 (6H, s), 1.56-1.61 (2H, m), 1.73-1.79 (2H, m), 2.42 (2H, s), 2.65-2.71 (2H, m), 3.19 (3H, s), 3.26-3.30(2H, m), 3.69 (2H, s), 6.59-6.65 (1H, m), 6.90-6.96 (1H, m), 7.27-7.34(1H, m), 7.56-7.61 (1H, m), 11.47 (1H, br s), 12.55 (1H, br s). 448 446184

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.22 (6H, s), 1.53-1.62 (2H, m), 2.42(2H, s), 2.65-2.70 (2H, m), 3.17-3.24 (2H, m), 3.20 (3H, s), 3.83 (2H,s), 3.97 (2H, s), 6.59-6.65 (1H, m), 6.91-6.96 (1H, m), 7.28- 7.36 (1H,m), 7.55-7.61 (1H, m), 11.45 (1H, br s), 12.55 (1H, br s). 464 462 185

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.53-1.62 (2H, m), 2.42 (2H, s),2.62-2.79 (4H, m), 3.15- 3.43 (2H, m), 3.19 (3H, s), 3.57 (2H, s), 6.29(1H, br s), 6.59-6.64 (1H, m), 6.89-6.94 (1H, m), 7.26- 7.32 (1H, m),7.55-7.61 (1H, m), 11.43 (1H, br s), 12.46 (1H, br s). 421 419 186

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.61 (2H, m), 2.41 (2H, s), 2.61(3H, s), 2.65-2.71 (2H, m), 3.14-3.26 (2H, m), 3.18 (3H, s), 3.28-3.36(2H, m), 3.59 (2H, s), 6.58-6.66 (1H, m), 6.87-6.96 (1H, m), 7.25-7.33(1H, m), 7.54-7.61 (1H, m), 11.44 (1H, br s), 12.54 (1H, br s). 435 433

TABLE 1-38 Ex. MS MS No. structural formula NMR (M + H) (M − H) 187

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.28-1.36 (2H, m), 1.39-1.50 (4H, m),1.53-1.62 (4H, m), 2.35-2.44 (2H, m), 2.42 (2H, s), 2.64-2.70 (2H, m),3.18 (3H, s), 3.41- 3.47 (2H, m), 3.75 (2H, s), 6.58-6.63 (1H, m),6.90-6.96 (1H, m), 7.28- 7.33 (1H, m), 7.53-7.61 (1H, m), 11.44 (1H, brs), 12.53 (1H, br s). 462 460 188

¹H-NMR (DMSO-D₆) δ: 0.96-1.05 (3H, m), 1.01 (6H, s), 1.54-1.61 (2H, m),1.76-1.88 (1H, m), 2.27-2.40 (2H, m), 2.42 (2H, s), 2.64-2.71 (2H, m),2.92-2.98 (1H, m), 3.19 (3H, s), 3.42-3.49 (1H, m), 3.63-3.76 (2H, m),6.59-6.63 (1H, m), 6.90-6.96 (1H, m), 7.27- 7.32 (1H, m), 7.55-7.61 (1H,m), 11.46 (1H, br s), 12.54 (1H, br s). 434 432 189

¹H-NMR (DMSO-D₆) δ: 0.98 (6H, s), 1.01 (6H, s), 1.49-1.55 (2H, m),1.56-1.62 (2H, m), 1.98 (2H, s), 2.41 (2H, s), 2.63-2.72 (2H, m), 3.19(3H, s), 3.23-3.31 (2H, m), 3.76 (2H, s), 6.58- 6.64 (1H, m), 6.90-6.96(1H, m), 7.28-7.34 (1H, m), 7.55-7.61 (1H, m), 11.46 (1H, br s), 12.54(1H, br s). 462 460 190

¹H-NMR (DMSO-D₆) δ: 0.81-0.91 (3H, m), 1.00 (6H, s), 1.55-1.61 (2H, m),1.69-1.85 (2H, m), 2.41 (2H, s), 2.63-2.70 (2H, m), 3.00-3.58 (5H, m),3.32 (3H, s), 3.68- 3.99 (4H, m), 6.62-6.67 (1H, m), 6.93-7.00 (1H, m),7.31-7.36 (1H, m), 7.59-7.65 (1H, m), 10.09 (1H, br s), 11.47 (1H, brs), 12.57 (1H, br s). 450 448 191

¹H-NMR (DMSO-D₆) δ: 0.84 (3H, dd, J = 77.7, 38.8 Hz), 1.01 (6H, s),1.54-1.62 (2H, m), 1.69- 1.85 (2H, m), 2.42 (2H, s), 2.64-2.71 (2H, m),2.99-3.55 (5H, m), 3.33 (3H, s), 3.70-4.01 (4H, m), 6.61-6.67 (1H, m),6.92-7.01 (1H, m), 7.31- 7.38 (1H, m), 7.59-7.66 (1H, m), 10.14 (1H, brs), 11.48 (1H, br s), 12.58 (1H, br s). 450 448

TABLE 1-39 Ex. MS MS No. structural formula NMR (M + H) (M − H) 192

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 1.82-1.97 (3H, m),2.41 (2H, s), 2.65- 2.70 (2H, m), 2.70-2.95 (3H, m), 3.17-3.25 (3H, m),3.76-3.84 (2H, m), 6.59-6.63 (1H, m), 6.89- 6.98 (1H, m), 7.28-7.34 (1H,m), 7.55-7.61 (1H, m), 11.45 (1H, br s), 12.53 (1H, br s). 408 406 193

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.10-1.19 (6H, m), 1.55-1.61 (2H, m),2.23-2.45 (4H, m), 2.65-2.70 (2H, m), 2.73- 2.99 (3H, m), 3.18-3.24 (3H,m), 3.81-3.94 (2H, m), 4.77-4.82 (1H, m), 6.59-6.64 (1H, m), 6.91- 466464 6.98 (1H, m), 7.30-7.35 (1H, m), 7.55-7.60 (1H, m), 11.41 (1H, brs), 12.51 (1H, br s). 194

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.15-1.62 (8H, m), 1.78-1.87 (2H, m),2.14-2.64 (1H, m), 2.41 (2H, s), 2.65-2.70 (2H, m), 2.72-3.00 (3H, m),3.16-3.25 (6H, m), 3.34-3.38 (1H, m), 3.73- 506 504 3.87 (2H, m),6.59-6.64 (1H, m), 6.90-6.98 (1H, m), 7.28-7.35 (1H, m), 7.54-7.62 (1H,m), 11.34-11.49 (1H, m), 12.50 (1H, br s). 195

¹H-NMR (DMSO-D₆) δ: 0.95-1.08 (9H, m), 1.01 (6H, s), 1.26 (3H, s),1.54-1.60 (2H, m), 2.41 (2H, s), 2.55 (1H, s), 2.63-2.72 (2H, m), 2.66(1H, s), 3.18 (3H, s), 4.60-4.76 (1H, m), 6.54- 6.62 (1H, m), 6.82-6.92(1H, m), 7.21-7.31 (1H, m), 7.50-7.55 (1H, m), 11.39 (1H, br s), 12.50(1H, br s). 480 478 196

¹H-NMR (DMSO-D₆) δ: I. 01 (6H, s), 1.50-1.61 (3H, m), 1.94-2.07 (1H, m),2.12-2.27 (2H, m), 2.42 (2H, s), 2.65-2.71 (2H, m), 3.19 (3H, s), 3.20(3H, s), 3.25-3.35 (2H, m), 3.54-3.60 (1H, m), 3.74-3.82 (1H, m),3.89-3.97 (1H, m), 6.60- 6.64 (1H, m), 6.89-6.94 (1H, m), 7.29-7.33 (1H,m), 7.56-7.61 (1H, m), 11.43 (1H, br s), 12.52 (1H, br s). 464 462

TABLE 1-40 Ex. MS MS No. structural formula NMR (M + H) (M − H) 197

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.52-1.61 (3H, m), 1.96-2.06 (1H, m),2.12-2.26 (2H, m), 2.42 (2H, s), 2.64-2.72 (2H, m), 3.20 (3H, s), 3.20(3H, s), 3.25-3.37 (2H, m), 3.57 (1H, d, J = 16.5 Hz), 3.74-3.82 (1H,m), 3.93 (1H, d, J = 16.5 Hz), 6.59-6.64 (1H, m), 6.88-6.94 (1H, m),7.27- 7.33 (1H, m), 7.56-7.61 (1H, m), 11.43 (1H, br s), 12.51 (1H, brs). 464 462 198

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.55-1.61 (2H, m), 2.41 (2H, s),2.63-2.72 (2H, m), 2.76- 2.85 (3H, m), 3.20 (3H, s), 3.50-3.59 (3H, m),3.71 (2H, s), 6.58-6.65 (1H, m), 6.86-6.95 (1H, m), 7.24-7.33 (1H, m),7.54-7.61 (1H, m), 11.44 (1H, br s), 12.53 (1H, br s). 424 422 199

¹H-NMR (DMSO-D₆) δ: 0.88-0.98 (6H, m), 1.01 (6H, s), 1.55-1.61 (2H, m),2.41 (2H, s), 2.65- 2.70 (2H, m), 2.71-3.01 (4H, m), 3.16-3.25 (3H, m),3.75-3.89 (2H, m), 6.59-6.65 (1H, m), 6.90- 436 434 6.99 (1H, m),7.29-7.35 (1H, m), 7.55-7.61 (1H, m), 11.45 (1H, br s), 12.53 (1H, brs). 200

¹H-NMR (DMSO-D₆) δ: 0.62-0.73 (4H, m), 1.01 (6H, s), 1.54-1.62 (2H, m),1.87-1.95 (1H, m), 2.41 (2H, s), 2.65-2.71 (2H, m), 2.73-3.13 (3H, m),3.16-3.26 (3H, m), 3.79-4.04 (2H, m), 6.57- 6.64 (1H, m), 6.88-7.00 434432 (1H, m), 7.26-7.36 (1H, m), 7.53-7.61 (1H, m), 11.44 (1H, br s),12.53 (1H, br s). 201

¹H-NMR (DMSO-D₆) δ: 7.17 (3H, s), 7.42 (6H, s), 7.56 (3H, s), 7.95- 8.02(2H, m), 8.25-8.33 (1H, m), 8.55-8.64 (1H, m), 8.82 (2H, s), 9.05- 9.12(2H, m), 9.24-9.29 (1H, m), 9.61 (3H, s), 9.88-9.95 (1H, m), 421 41910.16-10.23 (1H, m), 12.99-13.04 (1H, m), 13.25-13.32 (1H, m),13.62-13.68 (1H, m), 13.95-13.99 (1H, m), 17.79 (1H, br s), 18.94 (1H,br s).

TABLE 1-41 Ex. MS MS No. structural formula NMR (M + H) (M − H) 202

¹H-NMR (DMSO-D₆) δ: 0.82-1.04 (9H, m), 1.40- 1.46 (2H, m), 1.62 (2H, s),2.27 (2H, s), 2.49-2.67 (6H, m), 3.00-3.07 (3H, m), 4.31-4.83 (1H, m),6.41- 6.47 (1H, m), 6.70-6.77 (1H, m), 7.09-7.13 (1H, m), 7.34-7.43 (1H,m), 11.20- 11.31 (1H, m), 12.35- 12.41 (1H, m). 422 420 203

¹H-NMR (DMSO-D₆) δ: 0.72 (t, 2H, J = 7.4 Hz), 0.91 (t, 1H, J = 6.8 Hz),1.01 (s, 6H), 1.04 (d, 2H, J = 7.1 Hz), 1.15 (d, 1H, J = 6.8 Hz), 1.58(t, 3H, J = 6.3 Hz), 1.97-2.12 (m, 2H), 2.41 (s, 2H), 2.67 (s, 3H), 2.78(s, 2H), 3.15-3.20 (m, 3H), 4.48-4.54 (m, 0.3H), 4.96-5.03 (m, 0.7H),6.55- 6.62 (m, 1H), 6.84-6.92 (m, 1H), 7.20-7.30 (m, 1H), 7.47-7.57 (m,1H), 11.28- 11.46 (m, 1H), 12.52 (br s, 1H). 436 434 204

¹H-NMR (DMSO-D₆) δ: 0.27-1.26 (10H, m), 1.01 (6H, s), 1.55-1.61 (2H, m),2.41 (2H, s), 2.61-2.91 (5H, m), 3.14-3.21 (3H, m), 4.61-5.04 (1H, m),6.55- 6.61 (1H, m), 6.87-6.95 (1H, m), 7.22-7.32 (1H, m), 7.47-7.59 (1H,m), 11.32- 11.47 (1H, m), 12.49- 12.55 (1H, m). 450 448 205

¹H-NMR (DMSO-D₆) δ: −0.21-1.75 (10H, m), 1.01 (6H, s), 2.41 (2H, s),2.63- 3.04 (5H, m), 3.13-3.23 (3H, m), 4.85-5.04 (1H, m), 6.54-6.60 (1H,m), 6.85- 6.92 (1H, m), 7.21-7.31 (1H, m), 7.47-7.56 (1H, m),11.31-11.41 (1H, m), 12.48-12.55 (1H, m). 448 446 206

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.06 (t, 3H, J = 7.25 Hz), 1.58 (t,2H, J = 6.45 Hz), 2.42 (s, 2H), 2.63-2.72 (m, 2H), 3.61- 3.74 (m, 4H),4.45 (t, 1H, J = 5.64 Hz), 6.61 (s, 1H), 6.83 (d, 1H, J = 7.86 Hz), 7.21(s, 1H), 7.55 (d, 1H, J = 7.86 Hz), 11.41 (s, 1H), 12.55 (s, 1H). 367365

TABLE 1-42 Ex. MS MS No. structural formula NMR (M + H) (M − H) 207

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.04 (t, 3H, J = 7.05 Hz), 1.58 (t,2H, J = 6.45 Hz), 2.42 (s, 2H), 2.67 (s, 2H), 3.17 (s, 3H), 3.62-3.72(m, 4H), 6.60 (s, 1H), 6.84 (d, 1H, J = 8.46 Hz), 7.21 (s, 1H), 7.55 (d,1H, J = 8.46 Hz), 11.41 (s, 1H), 12.54 (s, 1H). 381 379 208

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.57 (t, 2H, J = 6.45 Hz), 2.40 (s,2H), 2.65-2.67 (br m, 2H), 4.09 (t, 2H, J = 7.96 Hz), 4.43 (t, 2H, J =7.96 Hz), 6.53 (s, 1H), 7.16 (d, 1H, J = 8.87 Hz), 7.49 (d, 1H, J = 8.87Hz), 7.61 (s, 1H), 11.24 (s, 1H), 12.47 (s, 1H). 351 349 209

¹H-NMR (DMSO-D₆) δ: 0.89 (t, 3H, J = 7.42 Hz), 1.01 (s, 6H), 1.58 (t,2H, J = 6.25 Hz), 1.97 (q, 2H, J = 7.42 Hz), 2.41 (s, 2H), 2.63-2.71 (m,2H), 3.44-3.52 (m, 2H), 3.69 (t, 2H, J = 6.36 Hz), 4.63 (t, 1H, J = 5.64Hz), 6.59 (s, 1H), 6.86 (d, 1H, J = 8.46 Hz), 7.24 (s, 1H), 7.53 (d, 1H,J = 8.46 Hz), 11.37 (s, 1H), 12.52 (s, 1H). 381 379 210

¹H-NMR (DMSO-D₆) δ: 1.00 (s, 6H), 1.57 (t, 2H, J = 6.25 Hz), 2.08 (tt,2H, J = 7.05, 7.05 Hz), 2.40 (s, 2H), 2.46-2.51 (m, 2H), 2.59-2.72 (m,2H), 3.86 (t, 2H, J = 7.05 Hz), 6.52 (s, 1H), 349 347 7.20 (d, 1H, J =8.46 Hz), 7.46 (d, 1H, J = 8.46 Hz), 7.69 (s, 1H), 11.21 (s, 1H), 12.47(s, 1H). 211

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.25 Hz), 1.80-1.93(m, 4H), 2.39 (t, 2H, J = 6.25 Hz), 2.41 (s, 2H), 2.62-2.71 (m, 2H),3.56- 3.65 (m, 2H), 6.55 (s, 1H), 6.81 (d, 1H, J = 8.46 Hz), 363 3617.19 (s, 1H), 7.46 (d, 1H, J = 8.46 Hz), 11.30 (s, 1H), 12.50 (s, 1H).

TABLE 1-43 Ex. MS MS No. structural formula NMR (M + H) (M − H) 212

¹H-NMR (DMSO-D₆) δ: 0.89 (t, 3H, J = 7.42 Hz), 1.01 (s, 6H), 1.58 (t,2H, J = 6.25 Hz), 1.97 (q, 2H, J = 7.42 Hz), 2.41 (s, 2H), 2.62-2.72 (m,2H), 3.21 (s, 3H), 3.39 (t, 2H, J = 6.04 Hz), 3.39 (s, 2H), 3.79 (t, 2H,J = 6.04 Hz), 6.60 (s, 1H), 6.84 (d, 1H, J = 8.26 Hz), 7.24 (s, 1H),7.54 (d, 1H, J = 8.26 Hz), 11.38 (s, 1H), 12.53 (s, 1H). 395 393 213

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.18 Hz), 2.41 (s,2H), 2.63-2.70 (m, 2H), 3.17 (s, 3H), 3.48 (q, 2H, J = 6.03 Hz),3.64-3.74 (m, 4H), 4.67 (t, 1H, J = 5.62 Hz), 6.60 (s, 1H), 6.88 (d, 1H,J = 8.16 Hz), 7.27 (s, 1H), 7.53 (d, 1H, J = 8.16 Hz),11.41 (s, 1H),12.53 (s, 1H). 397 395 214

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.03 Hz), 1.72 (s,3H), 2.41 (s, 2H), 2.66 (t, 2H, J = 6.03 Hz), 3.47 (td, 2H, J = 6.40,6.00 Hz), 3.68 (t, 2H, J = 6.61 Hz), 4.64 (t, 1H, J = 5.68 Hz), 6.59 (s,1H), 6.88 (d, 1H, J = 8.23 Hz), 7.25 (s, 1H), 7.53 (d, 1H, J = 8.23 Hz),11.39 (s, 1H), 12.53 (s, 1H). 367 365 215

¹H-NMR (DMSO-D₆) δ: 0.75-0.90 (m, 2H), 0.98- 1.14 (m, 1H), 1.01 (s, 6H),1.29-1.42 (m, 2H), 1.42-1.50 (m, 1H), 1.51- 1.65 (m, 6H), 2.07-2.17 (m,1H), 2.11 (s, 6H), 2.29 (t, 2H, J = 7.05 Hz), 2.42 (s, 2H), 2.64-2.72(m, 2H), 3.61-3.76 (m, 2H), 6.60 (s, 1H), 6.84 (d, 1H, J = 8.26 Hz),7.24 (s, 1H), 7.55 (d, 1H, J = 8.26 Hz), 11.36 (s, 1H), 12.54 (s, 1H).462 460 216

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.38-1.48 (m, 2H), 1.54-1.73 (m, 4H),2.12 (s, 6H), 2.29- 2.31 (m, 1H), 2.35-2.44 (m, 3H), 2.42 (s, 2H),2.63-2.74 (m, 2H), 2.94 (t, 2H, J = 11.08 Hz), 3.64-3.78 (m, 4H), 6.61(s, 1H), 6.86 (d, 1H, J = 8.06 Hz), 7.26 (s, 1H), 7.56 (d, 1H, J = 8.06Hz), 11.37 (s, 1H), 12.54 (s, 1H). 464 462

TABLE 1-44 Ex. MS MS No. structural formula NMR (M + H) (M − H) 217

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.25 Hz), 1.66-1.78(m, 1H), 1.95-2.06 (m, 1H), 2.15 (s, 6H), 2.29- 2.38 (m, 2H), 2.41 (s,2H), 2.63-2.72 (m, 2H), 2.79-2.86 (m, 1H), 3.45- 3.52 (m, 1H), 3.53-3.64(m, 2H), 3.65-3.72 (m, 1H), 3.71-3.82 (br m, 1H), 6.61 (s, 1H), 6.87 (d,1H, J = 8.26 Hz), 7.26 (s, 1H), 7.56 (d, 1H, J = 8.26 Hz), 11.40 (s,1H), 12.54 (s, 1H). 450 448 218

¹H-NMR (DMSO-D₆) δ: 0.75-0.91 (m, 1H), 0.86 (t, 3H, J = 7.15 Hz), 1.01(s, 6H), 1.02-1.13 (m, 1H), 1.20-1.50 (m, 4H), 1.51- 1.65 (m, 8H), 2.07(s, 6H), 2.09-2.17 (m, 1H), 2.20 (t, 2H, J = 7.15 Hz), 2.42 (s, 2H),2.62-2.73 (m, 2H), 3.53-3.66 (m, 2H), 6.61 (s, 1H), 6.83 (d, 1H, J =7.86 Hz), 7.22 (s, 1H), 7.56 (d, 1H, J = 7.86 Hz), 11.35 (s, 1H), 12.54(s, 1H). 476 474 219

¹H-NMR (DMSO-D₆) δ: 0.62-0.76 (m, 2H), 1.01 (s, 7H), 1.08-1.22 (m, 2H),1.48-1.62 (m, 7H), 1.62-1.74 (m, 1H), 1.84 (d, 2H, J = 6.85 Hz), 2.12(s, 6H), 2.30 (t, 2H, J = 7.05 Hz), 2.42 (s, 2H), 2.63-2.73 (m, 2H),3.67-3.78 (m, 2H), 6.59 (s, 1H), 6.81 (d, 1H, J = 8.06 Hz), 7.21 (s,1H), 7.53 (d, 1H, J = 8.06 Hz), 11.38 (s, 1H), 12.53 (s, 1H). 476 474220

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.53-1.79 (m, 4H), 1.81-1.93 (m, 2H),2.13 (s, 6H), 2.30 (t, 2H, J = 7.05 Hz), 2.42 (s, 2H), 2.66 (t, 2H, J =6.04 Hz), 3.62 (td, 1H, J = 7.45, 4.30 Hz), 3.65- 3.77 (m, 2H), 3.81 (q,1H, J = 7.25 Hz), 4.11 (dd, 1H, J = 7.25, 5.64 Hz), 6.60 (s, 1H), 6.86(d, 1H, J = 8.26 Hz), 7.26 (s, 1H), 7.54 (d, 1H, J = 8.26 Hz), 11.41 (s,1H), 12.54 (s, 1H). 450 448

TABLE 1-45 Ex. MS MS No. structural formula NMR (M + H) (M − H) 221

¹H-NMR (DMSO-D₆) δ: 0.89-1.07 (2H, m), 1.01 (6H, s), 1.48 (2H, d, J =12.89 Hz), 1.57- 1.59 (2H, m), 1.89-1.92 (3H, m), 2.15 (6H, s), 2.34(2H, s), 2.42 (2H, s), 2.67 (2H, s), 3.14- 3.39 (2H, m), 3.73 (4H, d, J= 10.07 Hz), 3.92- 4.07 (0H, m), 6.61 (1H, s), 6.83 (1H, d, J = 7.66Hz), 7.23 (1H, s), 7.55 (1H, d, J = 7.66 Hz), 11.38 (1H, s), 12.53 (1H,s). 478 476 222

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.58 (2H, t, J = 6.25 Hz), 2.14 (6H,s), 2.30 (2H, t, J = 6.85 Hz), 2.42 (2H, s), 2.67 (2H, t, J = 5.84 Hz),3.17 (3H, s), 3.67 (2H, s), 3.72 (2H, t, J = 6.65 Hz), 6.60 (1H, s),6.86 (1H, d, J = 8.46 Hz), 7.26 (1H, s), 7.54 (1H, d, J = 8.46 Hz),11.42 (1H, s), 12.54 (1H, s). 424 422 223

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.41-1.44 (2H, m), 1.54-1.69 (6H, m),2.07 (6H, s), 2.20 (2H, t, J = 7.07 Hz), 2.36-2.43 (2H, m), 2.52-2.70(3H, m), 2.94 (2H, t, J = 11.02 Hz), 3.62 (2H, t, J = 7.30 Hz), 3.72(2H, dd, J = 11.36, 2.78 Hz), 6.61 (1H, s), 6.85 (1H, d, J = 8.12 Hz),7.23 (1H, s), 7.56 (1H, d, J = 8.12 Hz), 11.35 (1H, s), 12.54 (1H, s).478 476 224

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.56-1.75 (6H, m), 1.83-1.92 (2H, m),2.10 (6H, s), 2.24 (2H, t, J = 6.96 Hz), 2.41 (2H, s), 2.66 (2H, s),3.56-3.70 (3H, m), 3.81 (1H, q, J = 7.19 Hz), 4.12 (1H, dd, J = 7.54,5.68 Hz), 6.60 (1H, s), 6.85 (1H, d, J = 8.35 Hz), 7.23 (1H, s), 7.55(1H, d, J = 8.35 Hz), 11.40 (1H, s), 12.53 (1H, s). 464 462

TABLE 1-46 Ex. MS MS No. structural formula NMR (M + H) (M − H) 225

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.56-1.64 (4H, m), 1.71-1.75 (1H, m),1.98-2.03 (1H, m), 2.08 (6H, s), 2.22 (2H, t, J = 7.05 Hz), 2.41 (2H,s), 2.54-2.69 (3H, m), 2.79-2.87 (1H, m), 3.46-3.72 (6H, m), 6.62 (1H,s), 6.85 (1H, d, J = 8.06 Hz), 7.23 (1H, s), 7.57 (1H, d, J = 8.06 Hz),11.37 (1H, s), 12.53 (1H, s). 464 462 226

¹H-NMR (DMSO-D₆) δ: 0.94-1.03 (2H, m), 1.01 (6H, s), 1.48 (2H, d, J =11.69 Hz), 1.56-1.64 (4H, m), 1.91-1.92 (1H, m), 1.91 (2H, s), 2.10 (6H,s), 2.23 (2H, t, J = 7.05 Hz), 2.42 (2H, s), 2.65-2.69 (2H, m),3.20-3.26 (2H, m), 3.63-3.74 (4H, m), 6.61 (1H, s), 6.81 (1H, d, J =8.46 Hz), 7.20 (1H, s), 7.56 (1H, d, J = 8.46 Hz), 11.37 (1H, s), 12.53(1H, s). 492 490 227

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.57 (2H, t, J = 6.29 Hz), 1.87 (1H,dd, J = 12.24, 9.15 Hz), 2.36-2.47 (1H, m), 2.40 (2H, s), 2.65-2.67 (2H,m), 3.74-3.78 (2H, m), 4.25-4.34 (1H, m), 5.68 (1H, d, J = 5.73 Hz),6.53 (1H, s), 7.23 (1H, d, J = 8.38 Hz), 7.48 (1H, d, J = 8.38 Hz), 7.74(1H, s), 11.22 (1H, s), 12.46 (1H, s). 365 363 228

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.57 (2H, t, J = 6.29 Hz), 2.02-2.21(2H, m), 2.40 (2H, s), 2.62-2.73 (3H, m), 3.63- 3.75 (2H, m), 3.76-3.88(2H, m), 4.77 (1H, t, J = 5.18 Hz), 6.52 (1H, s), 7.21 (1H, d, J = 8.38Hz), 7.45 (1H, d, J = 8.38 Hz), 7.70 (1H, s), 11.21 (1H, s), 12.46 (1H,s). 379 377

TABLE 1-47 Ex. MS MS No. structural formula NMR (M + H) (M − H) 229

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.17 (3H, d, J = 7.19 Hz), 1.57 (2H,t, J = 6.38 Hz), 1.65-1.75 (1H, m), 2.29-2.35 (1H, m), 2.40 (2H, s),2.57- 2.70 (3H, m), 3.77-3.82 (2H, m), 6.52 (1H, s), 7.21 (1H, d, J =8.35 Hz), 7.46 (1H, d, J = 8.35 Hz), 7.70 (1H, s), 11.21 (1H, s), 12.46(1H, s). 363 361 230

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.06 (3H, s), 1.57 (2H, t, J = 6.29Hz), 1.78-1.85 (1H, m), 2.30-2.36 (1H, m), 2.40 (2H, s), 2.66 (2H, s),3.27-3.30 (1H, m), 3.58 (1H, dd, J = 10.26, 5.40 Hz), 3.78 (2H, t, J =7.17 Hz), 4.91 (1H, t, J = 5.40 Hz), 6.52 (1H, s), 7.23 (1H, d, J = 8.38Hz), 7.46 (1H, d, J = 8.38 Hz), 7.71 (1H, s), 11.21 (1H, s), 12.46 (1H,s). 393 391 231

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.24-1.40 (2H, m), 1.48-1.67 (8H, m),2.41 (2H, s), 2.49- 2.55 (1H, m), 2.66-2.69 (2H, m), 3.44-3.51 (2H, m),3.66-3.72 (2H, m), 4.59 (1H, t, J = 5.64 Hz), 6.60 (1H, s), 6.86 (1H, d,J = 8.06 Hz), 7.25 (1H, s), 7.53 (1H, d, J = 8.06 Hz), 11.31 (1H, s),12.50 (1H, s). 421 419 232

¹H-NMR (DMSO-D₆) δ: 0.92-1.01 (2H,m), 1.01 (6H, s), 1.47-1.50 (2H, m),1.55-1.60 (2H, m), 1.88-1.95 (1H, m), 1.92 (2H, s), 2.42 (2H, s),2.66-2.68 (2H, m), 3.19- 3.26 (2H, m), 3.44-3.51 (2H, m), 3.68-3.74 (4H,m), 4.62 (1H, t, J = 5.44 Hz), 6.60 (1H, s), 6.84 (1H, d, J = 8.46 Hz),7.22 (1H, s), 7.54 (1H, d, J = 8.46 Hz), 11.38 (1H, s), 12.53 (1H, s).451 449 233

¹H-NMR (DMSO-D₆) δ: 0.61-0.72 (2H, m), 1.01 (6H, s), 1.37-1.49 (2H, m),1.55-1.70 (4H, m), 1.84-1.93 (2H, m), 2.02- 2.14 (1H, m), 2.41 (2H, s),2.64-2.73 (2H, m), 2.95-3.04 (1H, m), 3.13 (3H, s), 3.41-3.49 (2H, m),3.63-3.70 (2H, m), 4.58 (1H, t, J = 5.24 Hz), 6.60 (1H, s), 6.86 (1H, d,J = 8.06 Hz), 7.25 (1H, s), 7.54 (1H, d, J = 8.06 Hz), 11.32 (1H, s),12.51 (1H, s). 465 463

TABLE 1-48 Ex. MS MS No. structural formula NMR (M + H) (M − H) 234

¹H-NMR (DMSO-D₆) δ: 0.64-0.77 (2H, m), 1.01 (6H, s), 1.35-1.47 (2H, m),1.54-1.65 (4H, m), 1.67-1.77 (2H, m), 1.98- 2.10 (1H, m), 2.42 (2H, s),2.63-2.75 (2H, m), 2.68 (2H, s), 3.17-3.29 (1H, m), 3.41-3.50 (2H, m),3.61-3.73 (0H, m), 4.31 (1H, d, J = 4.84 Hz), 4.57 (1H, t, J = 5.44 Hz),6.60 (1H, s), 6.85 (1H, d, J = 8.06 Hz), 7.25 (1H, s), 7.54 (1H, d, J =8.06 Hz), 11.32 (1H, s), 12.50 (1H, s). 451 449 235

¹H-NMR (DMSO-D₆) δ: 0.63-0.75 (2H, m), 0.94- 1.07 (1H, m), 1.01 (6H, s),1.07-1.21 (2H, m), 1.50-1.63 (7H, m), 1.64- 1.77 (1H, m), 1.86 (2H, d, J= 6.85 Hz), 2.42 (2H, s), 2.64-2.71 (2H, m), 3.46- 3.50 (2H, m),3.67-3.71 (2H, m), 4.58 (1H, t, J = 5.44 Hz), 6.59 (1H, s), 6.82 (1H, d,J = 8.06 Hz), 7.21 (1H, s), 7.53 (1H, d, J = 8.06 Hz), 11.33 (1H, s),12.50 (1H, s). 449 447 236

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.42-1.45 (2H, m), 1.57-1.70 (4H, m),2.37-2.46 (1H, m), 2.42 (2H, s), 2.66-2.69 (2H, m), 2.92-2.98 (2H, m),3.45-3.49 (2H, m), 3.67-3.74 (4H, m), 4.59 (1H, t, J = 5.64 Hz), 6.60(1H, s), 6.88 (1H, d, J = 8.06 Hz), 7.27 (1H, s), 7.54 (1H, d, J = 8.06Hz), 11.32 (1H, s), 12.50 (1H, s). 437 435 237

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.56-1.75 (4H, m), 1.82-1.94 (2H, m),2.41 (2H, s), 2.62- 2.72 (2H, m), 3.42-3.55 (2H, m), 3.57-3.74 (3H, m),3.81 (1H, q, J = 7.12 Hz), 4.14 (1H, dd, J = 7.25, 5.64 Hz), 4.63 (1H,t, J = 5.64 Hz), 6.59 (1H, s), 6.88 (1H, d, J = 8.06 Hz), 7.27 (1H, s),7.53 (1H, d, J = 8.06 Hz), 11.36 (1H, s), 12.50 (1H, s). 423 421

TABLE 1-49 Ex. MS MS No. structural formula NMR (M + H) (M − H) 238

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.54-1.62 (2H, m), 1.68-1.77 (1H, m),1.97-2.06 (1H, m), 2.42 (2H, s), 2.61-2.71 (2H, m), 2.80-2.88 (1H, m),3.45-3.76 (8H, m), 4.61 (1H, t, J = 5.44 Hz), 6.60 (1H, s), 6.88 (1H, d,J = 8.06 Hz), 7.26 (1H, s), 7.55 (1H, d, J = 8.06 Hz), 11.35 (1H, s),12.50 (1H, s). 423 421 239

¹H-NMR (DMSO-D₆) δ: 0.75-0.90 (2H, m), 0.98- 1.12 (1H, m), 1.01 (6H, s),1.31-1.47 (3H, m), 1.52-1.63 (6H, m), 2.08- 2.19 (1H, m), 2.41 (2H, s),2.63-2.71 (2H, m), 3.41-3.50 (3H, m), 3.62-3.73 (2H, m), 4.60 (1H, t, J= 5.62 Hz), 6.60 (1H, s), 6.85 (1H, d, J = 8.16 Hz), 7.24 (1H, s), 7.54(1H, d, J = 8.16 Hz), 11.34 (1H, s), 12.52 (1H, s). 435 433 240

¹H-NMR (DMSO-D₆) δ: 0.92-1.02 (2H, m), 1.01 (6H, s), 1.27-1.38 (2H, m),1.54-1.79 (6H, m), 2.11-2.23 (1H, m), 2.41 (2H, s), 2.65-2.71 (2H, m),3.18-3.23 (1H, m), 3.43-3.48 (2H, m), 3.64-3.67 (2H, m), 4.60 (1H, t, J= 5.62 Hz), 6.60 (1H, s), 6.86 (1H, d, J = 8.16 Hz), 7.25 (1H, s), 7.54(1H, d, J = 8.16 Hz), 8.31 (0H, s), 11.34 (1H, s), 12.52 (1H, s). 465463 241

¹H-NMR (DMSO-D₆) δ: 0.43-0.62 (1H, m), 0.67-0.90 (1H, m), 0.90 (3H, d, J= 6.62 Hz), 1.01 (6H, s), 1.05-1.19 (2H, m), 1.35-1.44 (1H, m),1.50-1.68 (6H, m), 1.94-2.07 (1H, m), 2.41 (2H, s), 2.63-2.71 (2H, m),3.43-3.53 (2H, m), 3.56-3.81 (2H, m), 4.61 (1H, t, J = 5.51 Hz), 6.59(1H, s), 6.82 (1H, d, J = 7.94 Hz), 7.23 (1H, s), 7.54 (1H, d, J = 7.94Hz), 11.34 (1H, s), 12.52 (1H, s). 463 461

TABLE 1-50 Ex. MS MS No. structural formula NMR (M + H) (M − H) 242

¹H-NMR (DMSO-D₆) δ: 0.74-1.20 (2H, m), 0.91 (3H, d, J = 6.62 Hz), 1.01(6H, s), 1.42- 1.71 (5H, m), 1.99- 2.10 (1H, m), 2.41 (2H, s), 2.64-2.71(2H, m), 3.16-3.23 (2H, m), 3.43-3.84 (6H, m), 4.62 (1H, t, J = 5.40Hz), 6.60 (1H, s), 6.84 (1H, d, J = 7.94 Hz), 7.24 (1H, s), 7.55 (1H, d,J = 7.94 Hz), 11.35 (1H, s), 12.52 (1H, s). 465 463 243

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.35 (3H, s), 1.54-1.60 (2H, m),2.01-2.07 (1H, m), 2.28-2.35 (1H, m), 2.41 (2H, s), 2.62-2.70 (2H, m),3.25 (3H, s), 3.72-3.86 (2H, m), 6.54 (1H, s), 7.22 (1H, d, J = 8.38Hz), 7.49 (1H, d, J = 8.38 Hz), 7.74 (1H, s), 11.25 (1H, s), 12.47 (1H,s). 393 391 244

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.30 (3H, s), 1.57 (2H, t, J = 6.40Hz), 2.09 (2H, t, J = 6.84 Hz), 2.41 (2H, s), 2.62- 2.70 (2H, m),3.67-3.85 (2H, m), 5.45 (1H, s), 6.53 (1H, s), 7.23 (1H, d, J = 8.38Hz), 7.48 (1H, d, J = 8.38 Hz), 7.74 (1H, s), 11.24 (1H, s), 12.46 (1H,s). 379 377 245

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.04-1.20 (1H, m), 1.30-1.51 (1H, m),1.58 (2H, t, J = 6.45 Hz), 1.64-1.74 (2H, m), 2.42 (2H, s), 2.50-2.57(1H, m), 2.64-2.70 (2H, m), 2.90-2.96 (1H, m), 3.03-3.14 (1H, m), 3.36-3.59 (3H, m), 3.62-3.79 (4H, m), 4.66-4.71 (2H, m), 6.60 (1H, s), 6.87(1H, d, J = 8.06 Hz), 7.27 (1H, s), 7.54 (1H, d, J = 8.06 Hz), 11.42(1H, s), 12.53 (1H, s). 467 465

TABLE 1-51 Ex. MS MS No. structural formula NMR (M + H) (M − H) 246

¹H-NMR (DMSO-D₆) δ: 0.98-1.16 (2H, m), 1.00 (6H, s), 1.28-1.53 (2H, m),1.57 (2H, t, J = 6.25 Hz), 1.73-1.83 (1H, m), 2.41 (2H, s), 2.63-2.70(2H, m), 2.95-3.00 (1H, m), 3.07-3.14 (1H, m), 3.44-3.78 (7H, m), 4.66(1H, t, J = 5.44 Hz), 4.91 (1H, d, J = 8.06 Hz), 6.60 (1H, s), 6.87 (1H,d, J = 8.06 Hz), 7.27 (1H, s), 7.53 (1H, d, J = 8.06 Hz), 11.40 (1H, s),12.52 (1H, s). 467 465 247

¹H-NMR DMSO-D₆) δ: 0.76 (6H, d, J = 6.85 Hz), 1.01 (6H, s), 1.58 (2H, t,J = 6.25 Hz), 1.87 (2H, d, J = 6.85 Hz), 1.95-1.99 (1H, m), 2.41 (2H,s), 2.63-2.70 (2H, m), 3.45- 3.51 (2H, m), 3.67-3.72 (2H, m), 4.54-4.68(1H, m), 6.60 (1H, s), 6.83 (1H, d, J = 8.46 Hz), 7.22 (1H, s), 7.53(1H, d, J = 8.46 Hz), 11.36 (1H, s), 12.52 (1H, s). 409 407 248

¹H-NMR (DMSO-D₆) δ: 0.94-1.08 (1H, m), 1.01 (6H, s), 1.21-1.33 (3H, m),1.49-1.61 (4H, m), 1.73-1.85 (2H, m), 2.09- 2.18 (1H, m), 2.41 (2H, s),2.64-2.71 (2H, m), 3.46 (2H, t, J = 6.65 Hz), 3.56-3.73 (3H, m), 6.61(1H, s), 6.86 (1H, dd, J = 8.46, 1.81 Hz), 7.25 (1H, s), 7.54 (1H, d, J= 8.46 Hz), 11.32 (1H, s, 12.52 (1H, s). 451 449 249

¹H-NMR (DMSO-D₆) δ: 0.92-1.01 (2H, m), 1.01 (6H, s), 1.47-1.50 (2H, m),1.55-1.60 (2H, m), 1.88-1.95 (1H, m), 1.92 (2H, s), 2.42 (2H, s),2.66-2.68 (2H, m), 3.19- 3.26 (2H, m), 3.44-3.51 (2H, m), 3.68-3.74 (4H,m), 4.62 (1H, t, J = 5.44 Hz), 6.60 (1H, s), 6.84 (1H, d, J = 8.46 Hz),7.22 (1H, s), 7.54 (1H, d, J = 8.46 Hz), 11.38 (1H, s), 12.53 (1H, s).451 449

TABLE 1-52 Ex. MS MS No. structural formula NMR (M + H) (M − H) 250

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.07-1.32 (5H, m), 1.49-1.95 (9H, m),2.05-2.14 (1H, m), 2.40 (2H,s), 2.50-2.58 (1H, m), 2.65 (2H, s),3.66-3.86 (2H, m), 6.52 (1H, s), 7.18 (1H, d, J = 8.12 Hz), 7.45 (1H, d,J = 8.12 Hz), 7.68 (1H, s), 11.19 (1H, s), 12.46 (1H, s). 431 429 251

¹H-NMR (DMSO-D₆) δ: 0.80-1.78 (14H, m), 1.00 (6H, s), 1.99-2.17 (1H, m),2.40 (2H, s), 2.59- 2.70 (2H, m), 3.46-3.82 (4H, m), 4.79 (1H, s), 6.52(1H, s), 7.20 (1H, d, J = 8.35 Hz), 7.45 (1H, d, J = 8.35 Hz), 7.70 (1H,s), 11.19 (1H, s), 12.46 (1H, s). 461 459 252

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.01 (3H, d, J = 6.72 Hz), 1.58 (2H,t, J = 6.25 Hz), 2.18-2.30 (2H, m), 2.39-2.48 (2H, m), 2.41 (2H, s),2.62- 2.71 (2H, m), 3.13 (1H, q, J = 6.72 Hz), 3.46- 3.52 (6H, m),3.59-3.78 (2H, m), 4.61 (1H, t, J = 5.44 Hz), 6.59 (1H, s), 6.89 (1H,s), 7.29 (1H, s), 7.52 (1H, d, J = 8.06 Hz), 11.33 (1H, s), 12.50 (1H,s). 466 464 253

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.58 (2H, t, J = 6.06 Hz), 1.67 (4H,s), 2.12-2.21 (2H, m), 2.42 (2H, s), 2.63- 2.73 (2H, m), 3.17-3.25 (2H,m), 3.44-3.52 (2H, m), 3.69 (2H, t, J = 6.51 Hz), 3.73 (2H, s), 4.65(1H, t, J = 5.73 Hz), 6.60 (1H, s), 6.92 (1H, d, J = 7.94 Hz), 7.31 (1H,s), 7.55 (1H, d, J = 7.94 Hz), 11.43 (1H, s), 12.53 (1H, s). 464 462 254

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.58 (2H, t, J = 6.25 Hz), 2.27-2.35(3H, m), 2.41 (2H, s), 2.67 (3H, t, J = 6.25 Hz), 2.83 (2H, s), 3.28(2H, s), 3.44-3.52 (4H, m), 3.68 (2H, t, J = 6.45 Hz), 4.61 (1H, t, J =5.64 Hz), 6.60 (1H, s), 6.88 (1H, d, J = 8.06 Hz), 7.29 (1H, s), 7.53(1H, d, J = 8.06 Hz), 11.33 (1H, s), 12.43 (1H, s). 452 450

TABLE 1-53 Ex. MS MS No. structural formula NMR (M + H) (M − H) 255

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.02 (3H, d, J = 6.45 Hz), 1.58 (2H,t, J = 6.25 Hz), 2.22-2.31 (2H, m), 2.39-2.48 (4H, m), 2.64-2.71 (2H,m), 3.13 (1H, q, J = 6.45 Hz), 3.42- 3.56 (6H, m), 3.60-3.79 (2H, m),4.62 (1H, t, J = 5.44 Hz), 6.60 (1H, s), 6.88 (1H, d, J = 8.46 Hz), 7.31(1H, s), 7.53 (1H, d, J = 8.46 Hz), 11.32 (1H, s), 12.50 (1H, s). 466464 256

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.43-1.68 (8H, m), 2.31-2.45 (4H, m),2.64-2.72 (2H, m), 3.31 (2H, s), 3.43-3.51 (2H, m), 3.68 (2H, t, J =6.51 Hz), 3.78 (2H, s), 4.64 (1H, t, J = 5.40 Hz), 6.61 (1H, s), 6.92(1H, d, J = 7.72 Hz), 7.32 (1H, s), 7.56 (1H, d, J = 7.72 Hz), 11.42(1H, s), 12.52 (1H, s). 478 476 257

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.01 (3H, d, J = 7.06 Hz), 1.43- 1.54(2H, m), 1.58 (1H, t, J = 6.29 Hz), 2.10-2.19 (1H, m), 2.24-2.35 (1H,m), 2.42 (2H, s), 2.64- 2.70 (2H, m), 3.23-3.30 (2H, m), 3.44-3.51 (2H,m), 3.64-3.73 (4H, m), 4.66 (1H, t, J = 5.62 Hz), 6.61 (1H, s), 6.92(1H, d, J = 8.38 Hz), 7.32 (1H, s), 7.57 (1H, d, J = 8.38 Hz), 11.45(1H, s), 12.53 (1H, s). 464 462 258

¹H-NMR (DMSO-D₆) δ: 0.96-1.07 (13H, m), 1.22- 1.32 (2H, m), 1.49-1.61(4H, m), 1.74-1.87 (2H, m), 2.06-2.19 (1H, m), 2.41 (2H, s), 2.64-2.71(2H, m), 3.58-3.68 (3H, m), 4.21 (1H, s), 6.60 (1H, s), 6.82 (1H, d, J =8.60 Hz), 7.20 (1H, s), 7.55 (1H, d, J = 8.60 Hz), 11.33 (1H, s), 12.52(1H, s). 435 433

TABLE 1-54 Ex. MS MS No. structural formula NMR (M + H) (M − H) 259

¹H-NMR (DMSO-D₆) δ: 0.95-1.07 (8H, m), 1.23-1.32 (2H, m), 1.48-1.62 (4H,m), 1.72-1.87 (2H, m), 2.09-2.20 (1H, m), 2.41 (2H, s), 2.62-2.72 (2H,m), 3.21 (3H, s), 3.38 (2H, t, J = 6.18 Hz), 3.59-3.65 (1H, m),3.71-3.82 (2H, m), 4.21 (1H, d, J = 2.87 Hz), 6.61 (1H, s), 6.84 (1H, d,J = 8.38 Hz), 7.25 (1H, s), 7.54 (1H, d, J = 8.38 Hz), 11.34 (1H, s),12.53 (1H, s). 465 463 260

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.05 (3H, t, J = 7.25 Hz), 1.24 (3H,d, J = 6.85 Hz), 1.58 (2H, t, J = 6.45 Hz), 2.42 (2H, s), 2.64-2.71 (2H,m), 3.16-3.23 (1H, m), 3.44-3.53 (1H, m), 3.63-3.84 (5H, m), 3.84-3.92(1H, m), 4.08 (1H, q, J = 6.85 Hz), 6.61 (1H, s), 6.88 (1H, d, J = 7.66Hz), 7.28 (1H, s), 7.58 (1H, d, J = 8.06 Hz), 11.41 (1H, s), 12.51 (1H,s). 464 462 261

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.02- 1.09 (6H, m), 1.58 (2H, t, J =6.25 Hz), 2.41 (2H, s), 2.64-2.72 (2H, m), 3.42-3.73 (5H, m), 3.78 (1H,dd, J = 11.48, 3.43 Hz), 4.00 (2H, dd, J = 18.54, 16.52 Hz), 4.08 (1H,d, J = 16.52 Hz), 6.62 (1H, s), 6.92 (1H, d, J = 8.46 Hz), 7.31 (1H, s),7.59 (1H, d, J = 8.46 Hz), 11.40 (1H, s), 12.51 (1H, s). 464 462 262

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.07 (3H, d, J = 6.45 Hz), 1.58 (2H,t, J = 6.45 Hz), 2.41 (2H, s), 2.65-2.71 (2H, m), 3.22 (3H, s), 3.41(2H, t, J = 6.04 Hz), 3.44-3.53 (2H, m), 3.57 (1H, dd, J = 11.48, 3.83Hz), 3.75-3.84 (3H, m), 4.00 (2H, dd, J = 18.33, 16.52 Hz), 4.10 (1H, d,J = 16.52 Hz), 6.62 (1H, s), 6.93 (1H, d, J = 8.06 Hz), 7.34 (1H, s),7.58 (1H, d, J = 8.06 Hz), 11.41 (1H, s), 12.51 (1H, s). 494 492

TABLE 1-55 Ex. MS MS No. structural formula NMR (M + H) (M − H) 263

¹H-NMR (DMSO-D₆) δ: 0.75-0.88 (1H, m), 0.91 (3H, d, J = 6.85 Hz),0.96-1.18 (11H, m), 1.45-1.54 (2H, m), 1.58 (2H, t, J = 6.45 Hz),1.60-1.71 (1H, m), 1.98-2.09 (1H, m), 2.41 (2H, s), 2.68 (2H, t, J =6.45 Hz), 3.20 (2H, t, J = 11.69 Hz), 3.58-3.83 (3H, m), 6.61 (1H, s),6.80 (1H, d, J = 8.46 Hz), 7.20 (1H, s), 7.57 (1H, d, J = 8.46 Hz),11.30 (1H, s), 12.49 (1H, s). 449 447 264

¹H-NMR (DMSO-D₆) δ: 0.75-0.89 (1H, m), 0.89 (3H, t, J = 8.66 Hz),0.97-1.19 (2H, m), 1.01 (6H, s), 1.45-1.55 (2H, m), 1.57-1.70 (1H, m),1.58 (2H, t, J = 6.25 Hz), 2.00-2.12 (1H, m), 2.41 (2H, s), 2.62-2.72(2H, m), 3.15-3.24 (5H, m), 3.36-3.47 (2H, m), 3.61-4.01 (3H, m), 6.61(1H, s), 6.82 (1H, d, J = 8.06 Hz), 7.25 (1H, s), 7.55 (1H, d, J = 8.06Hz), 11.32 (1H, s), 12.50 (1H, s). 479 477 265

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.24 (3H, d, J = 6.84 Hz), 1.58 (2H,t, J = 6.29 Hz), 2.42 (2H, s), 2.63-2.74 (2H, m), 3.15-3.25 (4H, m),3.39 (2H, t, J = 5.95 Hz), 3.43-3.53 (1H, m), 3.62-3.94 (6H, m), 4.08(1H, q, J = 6.76 Hz), 6.61 (1H, s), 6.90 (1H, d, J = 8.38 Hz), 7.31 (1H,s), 7.57 (1H, d, J = 8.38 Hz), 11.47 (1H, s), 12.54 (1H, s). 494 492 266

¹H-NMR (DMSO-D₆) δ: 0.93-1.04 (5H, m), 1.01 (6H, s), 1.27-1.36 (2H, m),1.55-1.79 (4H, m), 1.58 (2H, t, J = 6.38 Hz), 2.11-2.21 (1H, m), 2.41(2H, s), 2.63-2.72 (2H, m), 3.15 (3H, s), 3.18-3.23 (1H, m), 3.63 (2H,q, J = 6.96 Hz), 6.60 (1H, s), 6.82 (1H, d, J = 8.12 Hz), 7.20 (1H, s),7.55 (1H, d, J = 8.12 Hz), 11.35 (1H, s), 12.53 (1H, s). 449 447

TABLE 1-56 Ex. MS MS No. structural formula NMR (M + H) (M − H) 267

¹H-NMR (DMSO-D₆) δ: 0.92-1.05 (2H, m), 1.01 (6H, s), 1.27-1.36 (2H, m),1.51-1.81 (4H, m), 1.58 (2H, t, J = 6.26 Hz), 2.13-2.23 (1H, m), 2.41(2H, s), 2.63-2.72 (2H, m), 3.15 (3H, s), 3.18-3.23 (1H, m), 3.20 (3H,s), 3.38 (2H, t, J = 6.15 Hz), 3.69-3.82 (2H, m), 6.60 (1H, s), 6.84(1H, d, J = 8.35 Hz), 7.24 (1H, s), 7.54 (1H, d, J = 8.35 Hz), 11.36(1H, s), 12.53 (1H, s). 479 477 268

¹H-NMR (DMSO-D₆) δ: 0.92-1.09 (2H, m), 1.01 (6H, s), 1.04 (3H, t, J =7.05 Hz), 1.48 (2H, d, J = 12.89 Hz), 1.58 (2H, t, J = 6.45 Hz), 1.92(3H, s), 2.42 (2H, s), 2.67 (2H, t, J = 6.45 Hz), 3.18-3.27 (2H, m),3.67 (2H, q, J = 7.05 Hz), 3.68-3.76 (2H, m), 6.60 (1H, s), 6.79 (1H, d,J = 8.06 Hz), 7.18 (1H, s), 7.55 (1H, d, J = 8.06 Hz), 11.34 (1H, s),12.51 (1H, s). 435 433 269

¹H-NMR (DMSO-D₆) δ: 0.92-1.05 (2H, m), 1.01 (6H, s), 1.44-1.52 (2H, m),1.58 (2H, t, J = 6.25 Hz), 1.92 (3H, s), 2.42 (2H, s), 2.63-2.71 (2H,m), 3.18-3.27 (2H, m), 3.21 (3H, s), 3.40 (2H, t, J = 6.04 Hz),3.68-3.76 (2H, m), 3.76-3.84 (2H, m), 6.60 (1H, s), 6.81 (1H, d, J =8.46 Hz), 7.22 (1H, s), 7.54 (1H, d, J = 8.46 Hz), 11.35 (1H, s), 12.50(1H, s). 465 463 270

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.04 (3H, t, J = 6.98 Hz), 1.45-1.54(2H, m), 1.54-1.65 (6H, m), 2.34-2.41 (2H, m), 2.42 (2H, s), 2.63-2.71(2H, m), 3.28-3.34 (2H, m), 3.66 (2H, q, J = 6.98 Hz), 3.77 (2H, s),6.61 (1H, s), 6.87 (1H, d, J = 8.46 Hz), 7.27 (1H, s), 7.56 (1H, d, J =8.46 Hz), 11.39 (1H, s), 12.51 (1H, s). 462 460

TABLE 1-57 Ex. MS MS No. structural formula NMR (M + H) (M − H) 271

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.05 (3H, t, J = 7.05 Hz), 1.07 (3H,d, J = 6.04 Hz), 1.58 (2H, t, J = 6.04 Hz), 2.42 (2H, s), 2.67 (2H, t, J= 6.04 Hz), 3.46 (1H, d, J = 16.52 Hz), 3.47- 3.54 (1H, m), 3.54-3.61(1H, m), 3.61-3.73 (2H, m), 3.75-3.82 (1H, m), 3.95-4.05 (2H, m), 4.08(1H, d, J = 16.52 Hz), 6.61 (1H, s), 6.91 (1H, d, J = 8.06 Hz), 7.30(1H, s), 7.58 (1H, d, J = 8.06 Hz), 11.40 (1H, s), 12.51 (1H, s). 464462 272

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.07 (3H, d, J = 6.04 Hz), 1.58 (2H,t, J = 6.25 Hz), 2.42 (2H, s), 2.63-2.71 (2H, m), 3.22 (3H, s), 3.41(2H, t, J = 6.04 Hz), 3.43-3.53 (2H, m), 3.54-3.60 (1H, m), 3.73- 3.85(3H, m), 3.94-4.05 (2H, m), 4.10 (1H, d, J = 16.52 Hz), 6.61 (1H, s),6.93 (1H, d, J = 8.46 Hz), 7.34 (1H, s), 7.58 (1H, d, J = 8.46 Hz),11.42 (1H, s), 12.51 (1H, s). 494 492 273

¹H-NMR (DMSO-D₆) δ: 0.66-0.81 (1H, m), 0.94- 1.09 (2H, m), 1.01 (6H, s),1.04 (3H, t, J = 7.12 Hz), 1.21-1.38 (2H, m), 1.53-1.95 (8H, m), 2.42(2H, s), 2.61-2.73 (2H, m), 2.86-2.97 (1H, m), 3.09 (1H, s), 3.17 (2H,s), 3.66 (2H, q, J = 7.12 Hz), 6.61 (1H, s), 6.78 (1H, d, J = 8.06 Hz),7.17 (1H, s), 7.54 (1H, d, J = 8.46 Hz), 11.32 (1H, s), 12.51 (1H, s).463 461 274

¹H-NMR (DMSO-D₆) δ: 0.67-0.81 (1H, m), 0.92- 1.09 (2H, m), 1.01 (6H, s),1.21-1.38 (2H, m), 1.52-1.94 (8H, m), 2.41 (2H, s), 2.64-2.72 (2H, m),2.86-2.96 (1H, m), 3.09 (1H, s), 3.17 (2H, s), 3.21 (3H, s), 3.40 (2H,t, J = 6.04 Hz), 3.75-3.83 (2H, m), 6.59 (1H, s), 6.80 (1H, d, J = 7.66Hz), 7.21 (1H, s), 7.53 (1H, d, J = 7.66 Hz), 11.35 (1H, s), 12.50 (1H,s). 493 491

TABLE 1-58 Ex. MS MS No. structural formula NMR (M + H) (M − H) 275

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.01 (3H, d, J = 6.72 Hz), 1.06 (3H,t, J = 7.05 Hz), 1.58 (2H, t, J = 6.25 Hz), 2.21-2.31 (2H, m), 2.39-2.49(2H, m), 2.41 (2H, s), 2.63-2.70 (2H, m), 3.12 (1H, q, J = 6.72 Hz),3.48 (4H, t, J = 4.43 Hz), 3.60- 3.72 (2H, m), 6.59 (1H, s), 6.84 (1H,d, J = 8.87 Hz), 7.25 (1H, s), 7.54 (1H, d, J = 8.87 Hz), 11.33 (1H, s),12.50 (1H, s). 450 448 276

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.01 (3H, d, J = 6.85 Hz), 1.58 (2H,t, J = 6.45 Hz), 2.21-2.31 (2H, m), 2.39-2.48 (2H, m), 2.41 (2H, s),2.63-2.71 (2H, m), 3.14 (1H, q, J = 6.85 Hz), 3.23 (3H, s), 3.38-3.46(2H, m), 3.48 (4H, t, J = 4.43 Hz), 3.65-3.94 (2H, m), 6.59 (1H, s),6.86 (1H, br s), 7.30 (1H, s), 7.53 (1H, d, J = 8.06 Hz), 11.34 (1H, s),12.50 (1H, s). 480 478 277

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.05 (3H, t, J = 7.25 Hz), 1.22 (6H,s), 1.58 (2H, t, J = 6.25 Hz), 2.42 (2H, s), 2.65-2.71 (2H, m), 3.21(2H, s), 3.68 (2H, q, J = 7.25 Hz), 3.78 (2H, s), 3.97 (2H, s), 6.62(1H, s), 6.89 (1H, d, J = 8.46 Hz), 7.29 (1H, s), 7.59 (1H, d, J = 8.46Hz), 11.41 (1H, s), 12.51 (1H, s). 478 476 278

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.22 (6H, s), 1.58 (2H, t, J = 6.45Hz), 2.42 (2H, s), 2.68 (2H, t, J = 6.45 Hz), 3.20 (2H, s), 3.22 (3H,s), 3.40 (2H, t, J = 5.84 Hz), 3.79 (2H, s), 3.81 (2H, t, J = 5.84 Hz),3.97 (2H, s), 6.62 (1H, s), 6.90 (1H, d, J = 8.46 Hz), 7.33 (1H, s),7.58 (1H, d, J = 8.46 Hz), 11.42 (1H, s), 12.51 (1H, s). 508 506 279

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.05 (3H, t, J = 7.17 Hz), 1.13 (3H,d, J = 5.95 Hz), 1.58 (2H, t, J = 6.06 Hz), 2.41 (2H, s), 2.65- 2.71(2H, m), 3.15- 3.25 (2H, m), 3.63- 3.73 (3H, m), 3.80- 3.90 (2H, m),4.02 (2H, s), 6.62 (1H, s), 6.89 (1H, d, J = 8.38 Hz), 7.28 (1H, s),7.59 (1H, d, J = 8.38 Hz), 11.45 (1H, s), 12.54 (1H, s). 464 462

TABLE 1-59 Ex. MS MS No. structural formula NMR (M + H) (M − H) 280

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.13 (3H, d, J = 6.03 Hz), 1.58 (2H,t, J = 6.38 Hz), 2.42 (2H, s), 2.64-2.72 (2H, m), 3.14- 3.25 (5H, m),3.39 (2H, t, J = 6.03 Hz), 3.70 (1H, d, J = 16.70 Hz), 3.78-3.91 (4H,m), 4.02 (2H, s), 6.62 (1H, s), 6.90 (1H, d, J = 8.12 Hz), 7.32 (1H, s),7.58 (1H, d, J = 8.12 Hz), 11.47 (1H, s), 12.54 (1H, s). 494 492 281

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.44-1.66 (8H, m), 2.34-2.46 (4H, m),2.64-2.72 (2H, m), 3.21 (3H, s), 3.28-3.35 (2H, m), 3.39 (2H, t, J =6.03 Hz), 3.75-3.82 (4H, m), 6.61 (1H, s), 6.90 (1H, d, J = 8.12 Hz),7.31 (1H, s), 7.56 (1H, d, J = 8.12 Hz), 11.44 (1H, s), 12.54 (1H, s).492 490 282

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.05 (3H, t, J = 7.19 Hz), 1.13 (3H,d, J = 6.26 Hz), 1.58 (2H, t, J = 6.38 Hz), 2.42 (2H, s), 2.64-2.72 (2H,m), 3.14- 3.26 (2H, m), 3.62-3.74 (3H, m), 3.79-3.90 (2H, m), 4.02 (2H,s), 6.62 (1H, s), 6.89 (1H, d, J = 8.35 Hz), 7.28 (1H, s), 7.59 (1H, d,J = 8.35 Hz), 11.46 (1H, s), 12.54 (1H, s). 464 462 283

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.13 (3H, d, J = 6.26 Hz), 1.58 (2H,t, J = 6.26 Hz), 2.42 (2H, s), 2.64-2.71 (2H, m), 3.14- 3.26 (5H, m),3.39 (2H, t, J = 5.91 Hz), 3.70 (1H, d, J = 16.46 Hz), 3.77-3.91 (4H,m), 4.02 (2H, s), 6.62 (1H, s), 6.90 (1H, d, J = 8.35 Hz), 7.32 (1H, s),7.58 (1H, d, J = 8.35 Hz), 11.47 (1H, s), 12.55 (1H, s). 494 492

TABLE 1-60 Ex. MS MS No. structural formula NMR (M + H) (M − H) 284

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.01 (6H, s), 1.04 (3H, t, J = 7.28Hz), 1.58 (2H, t, J = 6.18 Hz), 1.75 (2H, t, J = 6.73 Hz), 2.42 (2H, s),2.64-2.71 (2H, m), 3.24-3.32 (2H, m), 3.64 (2H, s), 3.67 (2H, q, J =7.28 Hz), 6.62 (1H, s), 6.89 (1H, d, J = 8.16 Hz), 7.27 (1H, s), 7.59(1H, d, J = 8.16 Hz), 11.45 (1H, s), 12.54 (1H, s). 462 460 285

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.01 (6H, s), 1.58 (2H, t, J = 6.45Hz), 1.76 (2H, t, J = 6.85 Hz), 2.42 (2H, s), 2.64-2.71 (2H, m), 3.22(3H, s), 3.24-3.31 (2H, m), 3.39 (2H, t, J = 5.84 Hz), 3.65 (2H, s),3.80 (2H, t, J = 6.04 Hz), 6.62 (1H, s), 6.90 (1H, d, J = 7.66 Hz), 7.31(1H, s), 7.58 (1H, d, J = 8.46 Hz), 11.42 (1H, s), 12.51 (1H, s). 492490 286

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.58 (2H, t, J = 6.26 Hz), 2.42 (2H,s), 2.62-2.72 (2H, m), 3.22 (3H, s), 3.29- 3.36 (2H, m), 3.40 (2H, t, J= 5.91 Hz), 3.75-3.85 (6H, m), 4.00 (2H, s), 6.62 (1H, s), 6.91 (1H, d,J = 8.35 Hz), 7.32 (1H, s), 7.58 (1H, d, J = 8.35 Hz), 11.47 (1H, s),12.55 (1H, s). 480 478 287

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.58 (2H, t, J = 6.26 Hz), 1.63- 1.72(4H, m), 2.13- 2.20 (2H, m), 2.41 (2H, s), 2.64-2.72 (2H, m), 3.21 (5H,s), 3.39 (2H, t, J = 5.91 Hz), 3.73 (2H, s), 3.80 (2H, t, J = 5.91 Hz),6.61 (1H, s), 6.90 (1H, d, J = 8.35 Hz), 7.31 (1H, s), 7.57 (1H, d, J =8.35 Hz), 11.45 (1H, s), 12.54 (1H, s). 478 476

TABLE 1-61 Ex. MS MS No. structural formula NMR (M + H) (M − H) 288

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.05 (3H, t, J = 7.19 Hz), 1.58 (2H,t, J = 6.26 Hz), 2.42 (2H, s), 2.63-2.72 (2H, m), 3.28-3.36 (2H, m),3.68 (2H, q, J = 7.11 Hz), 3.75-3.82 (4H, m), 4.00 (2H, s), 6.62 (1H,s), 6.90 (1H, d, J = 8.12 Hz), 7.28 (1H, s), 7.59 (1H, d, J = 8.12 Hz),11.45 (1H, s), 12.54 (1H, s). 450 448 289

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.04 (3H, t, J = 7.19 Hz), 1.58 (2H,t, J = 6.26 Hz), 1.64- 1.71 (4H, m), 2.12-2.20 (2H, m), 2.41 (2H, s),2.64-2.71 (2H, m), 3.18- 3.25 (2H, m), 3.66 (2H, q, J = 7.19 Hz), 3.72(2H, s), 6.61 (1H, s), 6.88 (1H, d, J = 8.35 Hz), 7.27 (1H, s), 7.57(1H, d, J = 8.35 Hz), 11.44 (1H, s), 12.54 (1H, s). 448 446 290

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.04 (3H, t, J = 6.25 Hz), 1.08 (6H,s), 1.58 (2H, t, J = 6.45 Hz), 2.13 (2H, s), 2.41 (2H, s), 2.62-2.71(2H, m), 3.69 (2H, q, J = 6.25 Hz), 4.97 (1H, s), 6.60 (1H, s), 6.81(1H, d, J = 8.06 409 407 Hz), 7.19 (1H, s), 7.56 (1H, d, J = 8.06 Hz),11.39 (1H, s), 12.54 (1H, s). 291

¹H-NMR (DMSO-D₆) δ: 0.97-1.10 (3H, m), 1.01 (6H, s), 1.58 (2H, t, J =6.29 Hz), 1.95 (2H, s), 2.41 (2H, s), 2.64-2.70 (2H, m), 2.71 (2H, s),2.92 (2H, s), 3.62-3.80 (4H, m), 6.59-6.64 (1H, m), 6.85-6.93 (1H, m),7.24-7.31 (1H, m), 7.55- 7.62 (1H, m), 11.42 (1H, s), 12.54 (1H, s). 422420 292

¹H-NMR (DMSO-D₆) δ: 0.87-1.09 (6H, m), 1.01 (6H, s), 1.58 (2H, t, J =6.40 Hz), 2.04-2.31 (2H, m), 2.42 (2H, s), 2.64- 2.71 (2H, m), 2.73 (1H,s), 2.92 (2H, s), 3.61- 3.80 (4H, m), 6.59-6.63 (1H, m), 6.85-6.93 (1H,m), 7.24-7.30 (1H, m), 7.54-7.62 (1H, m), 11.43 (1H, s), 12.53 (1H, s).436 434

TABLE 1-62 Ex. MS MS No. structural formula NMR (M + H) (M − H) 293

¹H-NMR (DMSO-D₆) δ: 1.02 (s, 6H), 1.59 (t, 2H, J = 6.28 Hz), 2.42 (s,2H), 2.69 (s, 2H), 6.70 (s, 1H), 7.07 (dd, 1H, J = 11.59, 4.11 Hz),7.32-7.36 (m, 2H), 7.46 (d, 1H, J = 8.69 Hz), 7.71 (d, 1H, J = 8.21 Hz),7.81 (dd, 2H, J = 8.57, 1.09 Hz), 8.21 (s, 1H), 10.09 (s, 1H), 11.57 (s,1H), 12.56 (s, 1H). 385 383 294

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.16 Hz), 2.42 (s,2H), 2.68 (t, 2H, J = 6.04 Hz), 2.79 (d, 3H, J = 4.35 Hz), 6.63 (d, 1H,J = 1.21 Hz), 7.38 (d, 1H, J = 8.45 Hz), 7.57 (dd, 1H, J = 8.45, 1.69Hz), 8.04 (s, 1H), 8.22 (d, 1H, J = 4.59 Hz), 11.46 (s, 1H), 12.53 (s,1H). 323 321 295

¹H-NMR (DMSO-D₆) δ: 0.99 (s, 6H), 1.55 (t, 2H, J = 6.40 Hz), 2.39 (s,2H), 2.62 (s, 2H), 3.39 (s, 3H), 6.47 (s, 1H), 6.97 (d, 1H, J = 8.45Hz), 7.08-7.25 (m, 6H), 7.49 (s, 1H), 11.34 (s, 1H), 12.49 (s, 1H). 399397 296

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.40 Hz), 2.41 (s,2H), 2.67 (s, 2H), 2.99 (s, 6H), 6.62 (s, 1H), 7.11 (d, 1H, J = 8.21Hz), 7.40 (d, 1H, J = 8.21 Hz), 7.58 (s, 1H), 11.42 (s, 1H), 12.53 (s,1H). 337 335 297

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.28 Hz), 2.42 (s,2H), 2.68 (t, 2H, J = 5.92 Hz), 6.62 (s, 1H), 7.04 (s, 1H), 7.37 (d, 1H,J = 8.45 Hz), 7.62 (d, 1H, J = 8.45 Hz), 7.78 (s, 1H), 8.10 (s, 1H),11.47 (s, 1H), 12.53 (s, 1H). 309 307

TABLE 1-63 Ex. MS MS No. structural formula NMR (M + H) (M − H) 298

¹H-NMR (DMSO-D₆) δ: 1.02 (d, 6H, J = 8.58 Hz), 1.58 (t, 2H, J = 6.26Hz), 2.41 (s, 2H), 2.66 (d, 2H, J = 5.10 Hz), 3.57 (t, 8H, J = 15.07Hz), 6.63 (s, 1H), 7.12 (d, 1H, J = 8.58 Hz), 7.41 (d, 1H, J = 8.58 Hz),7.59 (s, 1H), 11.47 (s, 1H), 12.54 (s, 1H). 379 377 299

¹H-NMR (DMSO-D₆) δ: 0.92 (s, 9H), 1.01 (s, 6H), 1.09 (d, 3H, J = 6.84Hz), 1.58 (t, 2H, J = 5.95 Hz), 2.42 (s, 2H), 2.67 (s, 2H), 4.01 (dd,1H, J = 9.37, 6.95 Hz), 6.64 (s, 1H), 7.38 (d, 1H, J = 8.60 Hz), 7.57(dd, 1H, J = 8.60, 1.54 Hz), 7.73 (d, 1H, J = 9.26 Hz), 8.05 (s, 1H),11.44 (s, 1H), 12.53 (s, 1H). 393 391 300

¹H-NMR (DMSO-D₆) δ: 0.76 (s, 4H), 1.01 (s, 11H), 1.19 (d, 3H, J = 18.84Hz), 1.58 (t, 2H, J = 6.03 Hz), 2.41 (s, 2H), 2.68 (s, 2H), 2.82 (s,3H), 6.62 (s, 1H), 7.04 (s, 1H), 7.42-7.49 (m, 2H), 11.40 (s, 1H), 12.52(s, 1H). 407 405 301

¹H-NMR (DMSO-D₆) δ: 0.99 (d, 6H, J = 13.67 Hz), 1.40 (s, 2H), 1.58 (t,2H, J = 6.18 Hz), 1.69 (s, 1H), 1.88 (s, 1H), 2.41-2.51 (m, 3H),2.66-3.07 (m, 4H), 3.48 (d, 1H, J = 9.92 Hz), 3.84 (s, 1H), 4.88 (s,1H), 6.61 (s, 1H), 7.08 (d, 1H, J = 8.38 Hz), 7.39 (d, 1H, J = 8.38 Hz),7.55 (s, 1H), 11.44 (s, 1H), 12.54 (s, 1H). 393 391

TABLE 1-64 Ex. MS MS No. structural formula NMR (M + H) (M − H) 302

¹H-NMR (DMSO-D₆) δ: 1.02 (d, 6H, J = 11.69 Hz), 1.35 (d, 2H, J = 9.04Hz), 1.58 (t, 2H, J = 6.06 Hz), 1.74 (s, 2H), 2.41 (s, 2H), 2.67 (t, 2H,J = 5.84 Hz), 3.17 (dd, 2H, J = 16.32, 6.40 Hz), 3.70- 3.84 (m, 3H),4.77 (d, 1H, J = 3.97 Hz), 6.62 (s, 1H), 7.08 (dd, 1H, J = 8.38, 1.32Hz), 7.39 (d, 1H, J = 8.38 Hz), 7.54 (s, 1H), 11.45 (s, 1H), 12.54 (s,1H). 393 391 303

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (s, 2H), 2.42 (s, 2H), 2.68 (s,2H), 3.30-3.35 (m, 2H), 3.52 (q, 2H, J = 6.03 Hz), 4.71 (t, 1H, J = 5.51Hz), 6.63 (s, 1H), 7.38 (d, 1H, J = 838 Hz), 7.59 (d, 1H, J = 8.38 Hz),8.07 (s, 1H), 8.22 (s, 1H), 11.48 (s, 1H), 12.54 (s, 1H). 353 351 304

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.18 Hz), 2.41 (s,2H), 2.67 (s, 2H), 3.00 (s, 3H), 3.17 (dd, 1H, J = 5.29, 1.76 Hz),3.40-3.50 (m, 3H), 4.76 (t, 1H, J = 5.40 Hz), 6.60 (s, 1H), 7.10 (d, 1H,J = 8.38 Hz), 7.38 (d, 1H, J = 8.38 Hz), 7.57 (s, 1H), 11.42 (s, 1H),12.53 (s, 1H). 367 365 305

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.25 Hz), 2.42 (s,2H), 2.69 (s, 2H), 3.66 (s, 3H), 4.01 (d, 2H, J = 5.64 Hz), 6.66 (s,1H), 7.41 (d, 1H, J = 8.46 Hz), 7.61 (d, 1H, J = 8.46 Hz), 8.10 (s, 1H),8.75 (t, 1H, J = 381 379 5.64 Hz), 11.54 (s, 1H), 12.56 (s, 1H). 306

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.45 Hz), 2.42 (s,2H), 2.69 (t, 2H, J = 6.04 Hz), 3.92 (d, 2H, J = 5.64 Hz), 6.67 (d, 1H,J = 1.21 Hz), 7.41 (d, 1H, J = 8.46 Hz), 7.62 (dd, 1H, J = 8.46, 1.61Hz), 8.10 (s, 1H), 367 365 8.63 (t, 1H, J = 5.84 Hz), 11.50 (s, 1H),12.54 (s, 2H).

TABLE 1-65 Ex. MS MS No. structural formula NMR (M + H) (M − H) 307

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.10 (d, 6H, J = 6.18 Hz), 1.58 (t,2H, J = 6.29 Hz), 2.42 (s, 2H), 2.68 (s, 2H), 3.39 (q, 2H, J = 6.03 Hz),3.49 (t, 2H, J = 6.29 Hz), 3.55-3.61 (m, 1H), 6.63 (s, 1H), 7.38 (d, 1H,J = 8.38 Hz), 7.59 (d, 1H, J = 8.38 Hz), 8.06 (s, 1H), 8.27 (s, 1H),11.48 (s, 1H), 12.55 (s, 1H). 395 393 308

¹H-NMR (DMSO-D₆) δ: 0.87 (t, 3H, J = 7.39 Hz), 1.02 (s, 6H), 1.51- 1.58(m, 4H), 2.43 (s, 2H), 2.69 (s, 2H), 3.33-3.53 (m, 6H), 6.64 (s, 1H),7.39 (d, 1H, J = 8.38 Hz), 7.60 (d, 1H, J = 8.38 Hz), 8.07 (s, 1H), 8.30(s, 1H), 11.50 (s, 1H), 12.55 (s, 1H). 395 393 309

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.29 Hz), 2.42 (s,2H), 2.68 (s, 2H), 3.64 (q, 2H, J = 5.88 Hz), 4.12 (t, 2H, J = 6.06 Hz),6.64 (s, 1H), 6.91-6.99 (m, 3H), 7.27-7.32 (m, 2H), 7.39 (d, 1H, J =8.60 Hz), 7.62 (d, 1H, J = 8.82 Hz), 8.10 (s, 1H), 8.50 (t, 1H, J = 5.07Hz), 11.50 (s, 1H), 12.55 (s, 1H). 429 427 310

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.29 Hz), 2.42 (s,2H), 2.68 (t, 2H, J = 6.06 Hz), 3.28 (s, 3H), 3.43-3.48 (m, 4H), 6.63(d, 1H, J = 1.32 Hz), 7.38 (d, 1H, J = 8.60 Hz), 7.59 (dd, 1H, J = 8.60,1.54 Hz), 8.07 (s, 1H), 8.30 (t, 1H, J = 4.96 Hz), 11.49 (s, 1H), 12.54(s, 1H). 367 365 311

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.18 Hz), 2.41 (s,2H), 2.68 (s, 2H), 3.03 (s, 3H), 3.69 (s, 3H), 4.22 (s, 2H), 6.64 (s,1H), 7.13 (s, 1H), 7.45-7.54 (m, 2H), 11.48 (s, 1H), 12.55 (s, 1H). 395393 312

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.38 Hz), 2.41 (s,2H), 2.68 (t, 2H, J = 6.15 Hz), 3.02 (s, 3H), 4.03-4.14 (m, 2H), 6.64(s, 1H), 7.03-7.13 (m, 1H), 7.43-7.58 (m, 2H), 11.46 (s, 1H), 12.65 (s,2H). 381 379 313

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.29 Hz), 2.41 (s,2H), 2.67 (s, 2H), 2.99 (s, 3H), 3.26 (br s, 3H), 3.48 (br s, 4H), 6.61(s, 1H), 7.09 (d, 1H, J = 7.94 Hz), 7.39 (d, 1H, J = 8.16 Hz), 7.55 (s,1H), 11.43 (s, 1H), 12.53 (s, 1H). 381 379

TABLE 1-66 Ex. MS MS No. structural formula NMR (M + H) (M − H) 314

¹H-NMR (DMSO-D₆) δ: 1.00 (s, 6H), 1.57 (t, 2H, J = 6.29 Hz), 2.41 (s,2H), 2.66 (br s, 2H), 2.90 (s, 3H), 4.65 (s, 2H), 6.62 (s, 1H), 7.15-7.42 (m, 7H), 7.63 (s, 1H), 11.45 (s, 1H), 12.53 (s, 1H). 413 411 315

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.29 Hz), 2.42 (s,2H), 2.68 (br s, 2H), 4.49 (d, 2H, J = 5.95 Hz), 6.64 (s, 1H), 7.21-7.45 (m, 6H), 7.64 (d, 1H, J = 8.38 Hz), 8.13 (s, 1H), 8.86 (t, 1H, J =5.73 Hz), 11.50 (s, 1H), 12.55 (s, 1H). 399 397 316

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.25 Hz), 2.42 (s,2H), 2.68 (br s, 2H), 4.76 (d, 2H, J = 6.04 Hz), 6.66 (s, 1H), 7.42 (d,1H, J = 8.87 Hz), 7.63-7.72 (m, 3H), 8.14 (s, 1H), 9.21 (t, 1H, J = 5.64Hz), 11.55 (s, 1H), 12.56 (s, 1H). 406 404 317

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.25 Hz), 2.42 (s,2H), 2.69 (t, 2H, J = 6.25 Hz), 4.74 (d, 2H, J = 5.64 Hz), 6.66 (s, 1H),7.36-7.44 (m, 1H), 7.65 (d, 1H, J = 7.25 Hz), 8.14 (s, 1H), 8.58 (t, 1H,J = 3.02 Hz), 8.95 (s, 1H), 11.52 (s, 1H), 12.55 (s, 1H). 391 389 318

¹H-NMR (DMSO-D₆) δ: 1.02 (s, 6H), 1.59 (t, 2H, J = 6.25 Hz), 2.42 (s,2H), 2.68 (br s, 2H), 4.32 (d, 2H, J = 5.64 Hz), 6.50 (t, 1H, J = 1.41Hz), 6.64 (s, 1H), 7.39 (d, 1H, J = 8.46 Hz), 7.59-7.63 (m, 3H), 8.09(s, 1H), 8.66 (t, 1H, J = 5.84 Hz), 11.50 (s, 1H), 12.56 (s, 1H). 389387 319

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.25 Hz), 2.41 (s,2H), 2.68 (t, 2H, J = 6.25 Hz), 3.60 (s, 3H), 4.45 (d, 2H, J = 5.24 Hz),5.89 (dd, 1H, J = 3.43, 2.62 Hz), 5.97 (dd, 1H, J = 3.43, 1.81 Hz), 6.64(dd, 2H, J = 5.04, 3.02 Hz), 7.38 (d, 1H, J = 8.46 Hz), 7.62 (dd, 1H, J= 8.46, 1.61 Hz), 8.10 (d, 1H, J = 1.21 Hz), 8.55 (t, 1H, J = 5.44 Hz),11.51 (s, 1H). 402 400

TABLE 1-67 Ex. MS MS No. structural formula NMR (M + H) (M − H) 320

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.33 (s, 6H), 1.58 (t, 2H, J = 6.25Hz), 2.41 (s, 2H), 2.67 (s, 2H), 3.51 (s, 2H), 4.97-5.10 (m, 1H), 6.63(s, 1H), 7.36-7.37 (m, 2H), 7.53 (d, 1H, J = 8.46 Hz), 8.01 (s, 1H),11.47 (s, 1H), 12.54 (s, 1H). 381 379 321

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.25 Hz), 2.42 (s,2H), 2.68 (t, 2H, J = 5.64 Hz), 3.26 (s, 3H), 3.56 (s, 3H), 6.66 (s,1H), 7.34-7.43 (m, 2H), 7.85 (s, 1H), 11.50 (s, 1H), 12.55 (s, 1H). 353351 322

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.25 Hz), 2.44- 2.48(m, 8H), 2.68 (s, 2H), 3.40 (q, 2H, J = 6.58 Hz), 3.58 (t, 4H, J = 4.43Hz), 6.63 (s, 1H), 7.38 (d, 1H, J = 8.46 Hz), 7.57 (d, 1H, J = 9.27 Hz),8.05 (s, 1H), 8.20 (t, 1H, J = 5.44 Hz), 11.49 (s, 1H), 12.55 (s, 1H).422 420 323

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.25 Hz), 2.25 (s,6H), 2.42 (s, 2H), 2.68 (s, 2H), 3.38 (q, 4H, J = 6.45 Hz), 6.64 (s,1H), 7.38 (d, 1H, J = 8.06 Hz), 7.58 (d, 1H, J = 8.06 Hz), 8.05 (s, 1H),8.20 (s, 1H), 11.49 (s, 1H), 12.55 (s, 1H). 380 378 324

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.59 (t, 2H, J = 6.25 Hz), 2.42 (s,2H), 2.69 (t, 2H, J = 5.84 Hz), 6.69 (s, 1H), 7.45 (d, 1H, J = 8.66 Hz),7.75 (dd, 1H, J = 8.66, 1.41 Hz), 8.29 (s, 1H), 11.69 (s, 1H), 12.02 (brs, 1H), 12.24 (br s, 1H), 12.60 (s, 1H). 409 407 325

¹H-NMR (DMSO-D₆) δ: 1.02 (s, 6H), 1.59 (t, 2H, J = 6.04 Hz), 2.42 (s,2H), 2.70 (s, 2H), 4.10 (s, 3H), 6.70 (s, 1H), 7.47 (d, 1H, J = 8.87Hz), 7.83 (d, 1H, J = 8.87 Hz), 8.38 (s, 1H), 11.70 (s, 1H), 12.55-12.60 (m, 2H). 423 421 326

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.47 (s, 6H), 1.59 (t, 2H, J = 6.25Hz), 2.42 (s, 2H), 2.68 (t, 2H, J = 5.84 Hz), 6.65 (s, 1H), 7.39 (d, 1H,J = 8.66 Hz), 7.59 (dd, 1H, J = 8.66, 1.81 Hz), 8.09 (s, 1H), 8.24 (s,1H), 11.47 (s, 1H). 395 393

TABLE 1-68 Ex. MS MS No. structural formula NMR (M + H) (M − H) 327

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.36 (s, 9H), 1.44 (s, 6H), 1.59 (t,2H, J = 6.25 Hz), 2.42 (s, 2H), 2.68 (d, 2H, J = 6.04 Hz), 6.64 (s, 1H),7.38 (d, 1H, J = 8.46 Hz), 7.56 (d, 1H, J = 8.46 Hz), 8.05 (s, 1H), 8.24(s, 1H), 11.49 (s, 1H), 12.55 (s, 1H). 451 449 328

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.25 Hz), 2.42 (s,2H), 2.67 (s, 2H), 3.54 (t, 4H, J = 5.84 Hz), 3.98 (dd, 1H, J = 13.70,6.04 Hz), 4.65 (t, 2H, J = 5.84 Hz), 6.64 (s, 1H), 7.38 (d, 1H, J = 8.06Hz), 7.60 (d, 1H, J = 9.27 Hz), 7.72 (d, 1H, J = 8.06 Hz), 8.09 (s, 1H),11.49 (s, 1H), 12.55 (s, 1H). 383 381 329

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.45 Hz), 2.41 (s,2H), 2.67 (s, 2H), 3.64 (s, 3H), 4.47 (d, 2H, J = 5.64 Hz), 6.63 (s,1H), 6.83 (s, 1H), 7.38 (d, 1H, J = 8.46 Hz), 7.54 (s, 1H), 7.61 (d, 1H,J = 8.46 Hz), 8.09 (s, 1H), 8.63 (s, 1H), 11.50 (s, 1H), 12.55 (s, 1H).403 401 330

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.11 (t, 6H, J = 6.65 Hz), 1.58 (t,2H, J = 6.45 Hz), 2.41 (s, 2H), 2.63-2.72 (m, 2H), 3.25-3.46 (br m, 4H),6.61 (s, 1H), 7.04 (d, 1H, J = 8.06 Hz), 7.39 (d, 1H, J = 8.06 Hz), 7.50(s, 1H), 11.42 (s, 1H), 12.54 (s, 1H). 365 363 331

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.11 (t, 3H, J = 6.65 Hz), 1.58 (t,2H, J = 6.25 Hz), 2.41 (s, 2H), 2.68 (t, 2H, J = 6.25 Hz), 2.95 (s, 3H),3.34-3.36 (m, 2H), 6.63 (d, 1H, J = 1.21 Hz), 7.08 (dd, 1H, J = 8.46,1.21 Hz), 7.40 (d, 1H, J = 8.46 Hz), 7.54 (s, 1H), 11.40 (s, 1H). 351349 332

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.45 Hz), 1.84 (d,4H, J = 16.92 Hz), 2.41 (s, 2H), 2.66-2.68 (m, 2H), 3.48 (t, 4H, J =6.65 Hz), 6.62 (s, 1H), 7.24 (d, 1H, J = 8.46 Hz), 7.38 (d, 1H, J = 8.46Hz), 7.71 (s, 1H), 11.44 (s, 1H), 12.54 (s, 1H). 363 361

TABLE 1-69 Ex. MS MS No. structural formula NMR (M + H) (M − H) 333

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.52-1.62 (m, 8H), 2.41 (s, 2H),2.63-2.71 (m, 2H), 3.48 (s, 4H), 6.61 (s, 1H), 7.07 (d, 1H, J = 7.66Hz), 7.39 (d, 1H, J = 7.66 Hz), 7.53 (s, 1H), 11.44 (s, 1H), 12.54 (s,1H). 377 375 334

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.25 Hz), 2.42 (s,2H), 2.62-2.72 (m, 4H), 3.75 (br s, 2H), 4.52 (br s, 2H), 6.65 (s, 1H),7.15 (d, 1H, J = 8.46 Hz), 7.43 (d, 1H, J = 8.46 Hz), 7.49 (s, 1H), 7.62(s, 1H), 11.48 (s, 1H), 12.55 (s, 1H). 415 413 335

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.25 Hz), 2.41 (s,2H), 2.63-2.72 (m, 2H), 3.34-3.40 (m, 2H), 3.58 (d, 1H, J = 5.44 Hz),3.61 (d, 1H, J = 5.44 Hz), 3.98 (br s, 1H), 4.09 (br s, 1H), 4.92 (br s,2H), 6.63 (s, 1H), 7.22 (d, 1H, J = 8.06 Hz), 7.39 (d, 1H, J = 8.06 Hz),7.69 (s, 1H), 11.46 (s, 1H), 12.54 (s, 1H). 395 393 336

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.40 (d, 9H, J = 6.45 Hz), 1.58 (t,2H, J = 6.25 Hz), 2.42 (s, 2H), 2.63-2.71 (m, 2H), 3.38 (br s, 4H), 3.50(br s, 4H), 6.62 (s, 1H), 7.12 (d, 1H, J = 8.26 Hz), 7.41 (d, 1H, J =8.26 Hz), 7.59 (s, 1H), 11.47 (s, 1H), 12.55 (s, 1H). 478 476 337

¹H-NMR (DMSO-D₆) δ: 0.96-1.09 (m, 9H), 1.58 (t, 2H, J = 6.25 Hz),2.26-2.50 (m, 6H), 2.41 (s, 2H), 2.61-2.75 (m, 2H), 3.40-3.66 (m, 4H),6.63 (s, 1H), 7.10 (d, 1H, J = 8.46 Hz), 7.40 (d, 1H, J = 8.46 Hz), 7.56(s, 1H), 11.46 (s, 1H), 12.55 (s, 1H). 406 404 338

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.45 Hz), 2.41 (s,2H), 2.63-2.71 (m, 2H), 3.24 (s, 3H), 3.37 (s, 3H), 3.43-3.52 (m, 2H),3.57-3.71 (m, 2H), 3.84- 3.94 (m, 1H), 3.95-4.05 (m, 1H), 6.64 (s, 1H),7.24 (d, 1H, J = 8.26 Hz), 7.40 (d, 1H, J = 8.26 Hz), 7.71 (s, 1H),11.46 (s, 1H), 12.54 (s, 1H). 423 421

TABLE 1-70 Ex. MS MS No. structural formula NMR (M + H) (M − H) 339

¹H-NMR (DMSO-D₆) δ: 0.99 (s, 6H), 1.54 (d, 2H, J = 5.51 Hz), 2.39 (s,2H), 2.61 (s, 2H), 3.38 (s, 3H), 6.45 (s, 1H), 6.86 (d, 1H, J = 7.94Hz), 7.18-7.23 (m, 7H), 11.28 (s, 1H), 12.50 (s, 1H). 399 397 340

¹H-NMR (DMSO-D₆) δ: 0.89 (t, 3H, J = 7.54 Hz), 1.01 (s, 6H), 1.59 (d,2H, J = 6.40 Hz), 1.99 (q, 2H, J = 7.66 Hz), 2.41 (s, 2H), 2.67 (s, 1H),3.17 (s, 4H), 6.58 (s, 1H), 6.94 (d, 1H, J = 9.04 Hz), 7.41 (s, 2H),11.39 (s, 1H), 12.54 (s, 1H). 351 349 341

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.41-1.66 (m, 6H), 2.41 (s, 3H), 2.67(s, 2H), 2.94 (t, 2H, J = 11.68 Hz), 3.16 (s, 3H), 3.72 (d, 2H, J = 9.42Hz), 6.60 (s, 1H), 6.96 (d, 1H, J = 9.42 Hz), 7.41-7.45 (m, 2H), 11.45(s, 1H), 12.55 (s, 1H). 407 405 342

¹H-NMR (DMSO-D₆) δ: 0.75 (d, 6H, J = 6.40 Hz), 1.01 (s, 6H), 1.58 (t,2H, J = 6.29 Hz), 1.91-1.97 (m, 3H), 2.42 (s, 2H), 2.66 (d, 2H, J = 5.95Hz), 3.18 (s, 3H), 6.58 (s, 1H), 6.90 (d, 1H, J = 8.38 Hz), 7.38- 7.41(m, 2H), 11.41 (s, 1H), 12.54 (s, 1H). 379 377

TABLE 1-71 Ex. MS MS No. structural formula NMR (M + H) (M − H) 343

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.29 Hz), 2.41 (s,2H), 2.67 (s, 2H), 3.20 (t, 4H, J = 14.00 Hz), 3.69 (s, 2H), 6.58 (s,1H), 6.95 (d, 1H, J = 7.94 Hz), 7.41-7.43 (m, 2H), 11.43 (s, 1H), 12.54(s, 1H). 353 351 344

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 6H), 1.58 (t, 2H, J = 6.29 Hz), 2.41 (s,2H), 2.67 (d, 2H, J = 4.85 Hz), 6.55 (s, 1H), 7.35 (d, 2H, J = 5.51 Hz),7.50-7.58 (m, 3H), 7.95-7.98 (m, 3H), 10.07 (s, 1H), 11.20 (s, 1H),12.49 (s, 1H). 385 383 345

¹H-NMR (DMSO-D₆) δ: 1.00 (s, 6H), 1.10 (t, 3H, J = 7.50 Hz), 1.57 (t,2H, J = 6.29 Hz), 2.30 (q, 2H, J = 7.57 Hz), 2.40 (s, 2H), 2.67 (d, 2H,J = 5.29 Hz), 6.49 (s, 1H), 7.16-7.26 (m, 2H), 7.81 (s, 1H), 9.61 (s,1H), 11.11 (s, 1H), 12.47 (s, 1H). 337 335 346

¹H-NMR (DMSO-D₆) δ: 0.92 (3H, s), 0.96-1.06 (2H, m), 1.21-1.39 (2H, m),1.50-1.80 (6H, m), 2.21-2.33 (1H, m), 2.29 (1H, d, J = 16.52 Hz), 2.55(1H, d, J = 16.52 Hz), 2.57-2.73 (2H, m), 3.16 (6H, s), 3.18-3.24 (1H,m), 3.26 (2H, d, J = 5.24 Hz), 4.62 (1H, t, J = 5.24 Hz), 6.59 (1H, s),6.86 (1H, d, J = 7.66 Hz), 7.23 (1H, s), 7.54 (1H, d, J = 7.66 Hz),11.32 (1H, s), 12.50 (1H, s). 451 449 347

¹H-NMR (DMSO-D₆) δ: 0.98 (3H, s), 1.53-1.75 (6H, m), 2.11-2.21 (2H, m),2.35 (1H, d, J = 16.12 Hz), 2.56 (1H, d, J = 15.72 Hz), 2.61-2.70 (2H,m), 3.15-3.26 (7H, m), 3.28 (3H, s), 3.77 (2H, s), 6.60 (1H, s), 6.92(1H, d, J = 7.66 Hz), 7.29 (1H, s), 7.56 (1H, d, J = 7.66 Hz), 11.45(1H, s), 12.55 (1H, s). 464 462

TABLE 1-72 Ex. MS MS No. structural formula NMR (M + H) (M − H) 348

¹H-NMR (DMSO-D₆) δ: 0.95-1.06 (2H, m), 0.98 (3H, s), 1.28-1.36 (2H, m),1.54-1.79 (6H, m), 2.20- 2.29 (1H, m), 2.35 (1H, d, J = 16.12 Hz), 2.56(1H, d, J = 16.12 Hz), 2.62-2.70 (2H, m), 3.15 (6H, s), 3.19 (2H, s),3.19-3.24 (1H, m), 3.28 (3H, s), 6.60 (1H, s), 6.86 (1H, d, J = 8.06Hz), 7.23 (1H, s), 7.55 (1H, d, J = 8.06 Hz), 11.36 (1H, s), 12.54 (1H,s). 465 463 349

¹H-NMR (DMSO-D₆) δ: 0.92 (3H, s), 1.21-1.39 (2H, m), 1.46-1.72 (8H, m),2.29 (1H, d, J = 15.88 Hz), 2.43-2.75 (4H, m), 3.18 (3H, s), 3.23-3.29(2H, m), 4.65 (1H, t, J = 4.96 Hz), 6.58 (1H, s), 6.86 (1H, d, J = 8.38Hz), 7.23 (1H, s), 7.54 (1H, d, J = 8.38 Hz), 11.36 (1H, s), 12.52 (1H,s). 407 405 350

¹H-NMR (DMSO-D₆) δ: 1.68-1.81 (m, 4H), 2.56- 2.68 (m, 4H), 3.39 (s, 3H),6.46 (s, 1H), 6.81 (d, 1H, J = 8.35 Hz), 7.07 (s, 1H), 7.12-7.23 (m,3H), 7.28 (d, 2H, J = 6.72 Hz), 7.37 (d, 1H, J = 8.35 Hz), 11.23 (s,1H), 12.52 (s, 1H). 371 369 351

¹H-NMR (DMSO-D₆) δ: 0.91 (t, 3H, J = 7.42 Hz), 1.73-1.83 (m, 4H), 2.01(q, 2H, J = 7.42 Hz), 2.58- 2.71 (m, 4H), 3.18 (s, 3H), 6.56 (s, 1H),6.86 (d, 1H, J = 8.12 Hz), 7.22 (s, 1H), 7.54 (d, 1H, J = 8.12 Hz),11.40 (s, 1H), 12.57 (s, 1H). 323 321 352

¹H-NMR (DMSO-D₆) δ: 1.71-1.84 (m, 4H), 2.56- 2.74 (m, 4H), 3.18 (s, 3H),3.19 (s, 3H), 3.73 (s, 2H), 6.57 (s, 1H), 6.88 (d, 1H, J = 8.00 Hz),7.24 (s, 1H), 7.54 (d, 1H, J = 8.00 Hz), 11.43 (s, 1H), 12.58 (s, 1H).339 337

TABLE 1-73 Ex. MS MS No. structural formula NMR (M + H) (M − H) 353

¹H-NMR (DMSO-D₆) δ: 1.08 (d, 3H, J = 6.45 Hz), 1.34-1.49 (m, 1H), 1.82-1.97 (m, 2H), 2.15-2.27 (m, 1H), 2.58-2.69 (m, 1H), 2.70-2.82 (m, 2H),3.18 (s, 3H), 3.19 (s, 3H), 3.73 (s, 2H), 6.57 (s, 1H), 6.88 (d, 1H, J =8.26 Hz), 7.24 (s, 1H), 7.54 (d, 1H, J = 8.26 Hz), 11.42 (s, 1H), 12.55(s, 1H). 353 351 354

¹H-NMR (DMSO-D₆) δ: 0.91 (t, 3H, J = 7.42 Hz), 1.08 (d, 3H, J = 6.85Hz), 1.33-1.49 (m, 1H), 1.83- 1.95 (m, 2H), 2.01 (q, 2H, J = 7.42 Hz),2.15-2.27 (m, 1H), 2.57-2.69 (m, 1H), 2.69-2.82 (m, 2H), 3.17 (s, 3H),6.56 (s, 1H), 6.86 (d, 1H, J = 8.26 Hz), 7.22 (s, 1H), 7.54 (d, 1H, J =8.26 Hz), 11.38 (s, 1H), 12.54 (s, 1H). 337 335 355

¹H-NMR (DMSO-D₆) δ: 0.91 (t, 3H, J = 7.38 Hz), 1.08 (d, 3H, J = 6.49Hz), 1.34-1.49 (m, 1H), 1.83- 1.95 (m, 2H), 2.01 (q, 2H, J = 7.38 Hz),2.15-2.27 (m, 1H), 2.56-2.69 (m, 1H), 2.70-2.83 (m, 2H), 3.18 (s, 3H),6.57 (s, 1H), 6.86 (d, 1H, J = 8.12 Hz), 7.22 (s, 1H), 7.54 (d, 1H, J =8.12 Hz), 11.40 (s, 1H), 12.55 (s, 1H). 337 335 356

¹H-NMR (DMSO-D₆) δ: 1.08 (d, 3H, J = 6.62 Hz), 1.34-1.50 (m, 1H), 1.83-1.98 (m, 2H), 2.15-2.27 (m, 1H), 2.58-2.69 (m, 1H), 2.70-2.84 (m, 2H),3.18 (s, 3H), 3.19 (s, 3H), 3.73 (s, 2H), 6.57 (s, 1H), 6.88 (d, 1H, J =7.83 Hz), 7.24 (s, 1H), 7.54 (d, 1H, J = 7.83 Hz), 11.42 (s, 1H), 12.54(s, 1H). 353 351 357

¹H-NMR (DMSO-D₆) δ: 1.06 (d, 3H, J = 6.49 Hz), 1.31-1.47 (m, 1H), 1.80-1.94 (m, 2H), 2.13-2.25 (m, 1H), 2.53-2.64 (m, 1H), 2.65-2.78 (m, 2H),3.39 (s, 3H), 6.46 (s, 1H), 6.81 (d, 1H, J = 8.23 Hz), 7.07 (s, 1H),7.15-7.19 (m, 3H), 7.28 (d, 2H, J = 6.72 Hz), 7.37 (d, 1H, J = 8.23 Hz),11.23 (s, 1H), 12.50 (s, 1H). 385 383

TABLE 1-74 Ex. MS MS No. structural formula NMR (M + H) (M − H) 358

¹H-NMR (DMSO-D₆) δ: 1.06 (d, 3H, J = 6.49 Hz), 1.31-1.47 (m, 1H),1.79-1.94 (m, 2H), 2.11- 2.25 (m, 1H), 2.55-2.64 (m, 1H), 2.65-2.78 (m,2H), 3.39 (s, 3H), 6.46 (s, 1H), 6.81 (d, 1H, J = 8.23 Hz), 7.07 (s,1H), 7.12-7.23 (m, 3H), 7.28 (d, 2H, J = 6.49 Hz), 7.37 (d, 1H, J = 8.23Hz), 11.23 (s, 1H), 12.50 (s, 1H). 385 383 359

¹H-NMR (DMSO-D₆) δ: 0.95 (d, 6H, J = 5.95 Hz), 1.72-1.84 (m, 4H),2.59-2.73 (m, 4H), 3.18 (s, 3H), 3.39-3.48 (m, 1H), 3.75 (s, 2H), 6.57(s, 1H), 6.88 (d, 1H, J = 8.16 Hz), 7.25 (s, 1H), 7.54 (d, 1H, J = 8.16Hz), 11.41 (s, 1H), 12.56 (s, 1H). 367 365 360

¹H-NMR (DMSO-D₆) δ: 1.75 (s, 3H), 1.76-1.82 (m, 4H), 2.57-2.72 (m, 4H),3.17 (s, 3H), 6.56 (s, 1H), 6.88 (d, 1H, J = 8.12 Hz), 7.23 (s, 1H),7.54 (d, 1H, J = 8.12 Hz), 11.40 (s, 1H), 12.57 (s, 1H). 309 307 361

¹H-NMR (DMSO-D₆) δ: 0.76 (d, 6H, J = 6.49 Hz), 1.72-1.84 (m, 4H), 1.91(d, 2H, J = 6.72 Hz), 1.92-2.04 (m, 1H), 2.57-2.73 (m, 4H), 3.18 (s,3H), 6.56 (s, 1H), 6.83 (d, 1H, J = 8.23 Hz), 7.19 (s, 1H), 7.54 (d, 1H,J = 8.23 Hz), 11.39 (s, 1H), 12.57 (s, 1H). 351 349 362

¹H-NMR (DMSO-D₆) δ: 1.74-1.82 (m, 4H), 2.58- 2.72 (m, 4H), 3.23 (s, 3H),4.42 (s, 2H), 6.59 (s, 1H), 6.75 (d, 2H, J = 7.88 Hz), 6.90 (t, 1H, J =7.30 Hz), 7.02 (d, 1H, J = 7.65 Hz), 7.23 (t, 2H, J = 7.88 Hz), 7.38 (s,1H), 7.59 (d, 1H, J = 8.35 Hz), 11.47 (s, 1H), 12.58 (s, 1H). 401 399

TABLE 1-75 Ex. MS MS No. structural formula NMR (M + H) (M − H) 363

¹H-NMR (DMSO-D₆) δ: 1.01 (s, 3H), 1.04 (s, 3H), 2.48 (dd, 2H, J = 53.80,15.92 Hz), 2.72- 3.04 (m, 2H), 3.51 (t, 1H, J = 5.04 Hz), 4.61 (dd, 2H,J = 85.63, 11.89 Hz), 5.09 (s, 2H), 6.59 (s, 1H), 6.89 (d, 1H, J = 8.26Hz), 7.22- 7.39 (m, 11H), 7.48 (d, 1H, J = 8.26 Hz), 11.29 (s, 1H),12.52 (s, 1H). 535 533 364

¹H-NMR (DMSO-D₆) δ: 0.91 (t, 3H, J = 7.29 Hz), 1.03 (d, 6H, J = 15.72Hz), 2.01 (q, 2H, J = 7.29 Hz), 2.49 (dd, 23H, J = 54.60, 15.92 Hz),2.74-3.03 (m, 2H), 3.18 (s, 3H), 3.51 (t, 1H, J = 5.04 Hz), 4.61 (dd,2H, J = 86.84, 11.89 Hz), 6.65 (s, 1H), 6.88 (d, 1H, J = 8.26 Hz),7.20-7.39 (m, 6H), 7.56 (d, 1H, J = 8.26 Hz), 11.38 (s, 1H), 12.58 (brs, 1H). 457 455 365

¹H-NMR (DMSO-D₆) δ: 0.91 (3H, t, J = 7.42 Hz), 1.76-1.90 (2H, m), 2.01(2H, q, J = 7.42 Hz), 2.51-2.77 (4H, m), 2.93 (2H, dd, J = 15.19, 4.29Hz), 3.18 (3H, s), 4.01-4.03 (1H, m), 4.84 (1H, d, J = 3.94 Hz), 6.55(1H, s), 6.87 (1H, d, J = 8.12 Hz), 7.23 (1H, s), 7.56 (1H, d, J = 8.12Hz), 11.39 (1H, s), 12.57 (1H, s). 339 337 366

¹H-NMR (DMSO-D₆) δ: 1.74-1.90 (2H, m), 2.53- 2.76 (5H, m), 2.90-2.94(1H, m), 3.17 (3H, s), 3.18 (3H, s), 3.73 (2H, s), 3.96-4.05 (1H, m),4.83 (1H, d, J = 3.71 Hz), 6.55 (1H, s), 6.89 (1H, d, J = 7.88 Hz), 7.24(1H, s), 7.55 (1H, d, J = 8.12 Hz), 11.42 (1H, s), 12.58 (1H, s). 355353 367

¹H-NMR (DMSO-D₆) δ: 1.69-1.89 (2H, m), 2.45- 2.74 (5H, m), 2.86-2.90(1H, m), 3.39 (3H, s), 3.93-4.02 (1H, m), 4.81 (1H, s), 6.44 (1H, s),6.81 (1H, d, J = 8.12 Hz), 7.07 (1H, s), 7.15- 7.18 (3H, m), 7.28 (2H,d, J = 6.49 Hz), 7.38 (1H, d, J = 8.12 Hz), 11.22 (1H, s), 12.52 (1H,s). 387 385

TABLE 1-76 Ex. MS MS No. structural formula NMR (M + H) (M − H) 368

¹H-NMR (DMSO-D₆) δ: 0.90 (3H, t, J = 7.42 Hz), 1.82-2.05 (2H, m), 2.00(4H, q, J = 7.42 Hz), 2.56- 2.75 (3H, m), 2.98-2.99 (1H, m), 3.17 (3H,s), 3.33 (3H, s), 3.72 (1H, d, J = 5.57 Hz), 6.59 (1H, s), 6.87 (1H, d,J = 8.58 Hz), 7.22 (1H, s), 7.55 (1H, d, J = 8.58 Hz), 11.39 (1H, s),12.60 (1H, s). 353 351 369

¹H-NMR (DMSO-D₆) δ: 1.85-1.98 (2H, m), 2.61- 2.72 (3H, m), 2.96-3.00(1H, m), 3.17 (3H, s), 3.18 (3H, s), 3.33 (2H, s), 3.69- 3.75 (1H, m),3.73 (3H, s), 6.60 (1H, s), 6.89 (1H, d, J = 8.12 Hz), 7.25 (1H, s),7.55 (1H, d, J = 8.12 Hz), 11.43 (1H, s), 12.61 (1H, s). 369 367 370

¹H-NMR (DMSO-D₆) δ: 1.85-1.93 (2H, m), 2.61- 2.65 (3H, m), 2.91-2.95(1H, m), 3.31 (3H, s), 3.39 (3H, s), 3.69 (1H, d, J = 5.80 Hz), 6.49(1H, s), 6.81 (1H, d, J = 8.58 Hz), 7.07 (1H, s), 7.15-7.18 (3H, m),7.27-7.28 (2H, m), 7.38 (1H, d, J = 8.58 Hz), 11.22 (1H, s), 12.55 (1H,s). 401 399 371

¹H-NMR (DMSO-D₆) δ: 0.90 (4H, t, J = 7.30 Hz), 1.10 (3H, d, J = 6.03Hz), 1.12 (3H, d, J = 6.03 Hz), 1.73-1.96 (2H, m), 2.01 (2H, q, J = 7.30Hz), 2.53- 2.71 (4H, m), 2.94-2.98 (1H, m), 3.17 (3H, s), 3.80 (1H,septd = 6.03 Hz), 3.84-3.94 (1H, m), 6.57 (1H, s), 6.86 (1H, d, J = 7.88Hz), 7.22 (1H, s), 7.54 (1H, d, J = 7.88 Hz), 11.37 (1H, s), 12.58 (1H,s). 381 379 372

¹H-NMR (DMSO-D₆) δ: 0.91 (3H, t, J = 7.39 Hz), 0.98 (3H, s), 1.01 (3H,s), 2.01 (2H, q, J = 7.39 Hz), 2.39 (1H, d, J = 16.10 Hz), 2.51 (9H, d,J = 16.10 Hz), 2.70 (1H, dd, J = 16.54, 5.07 Hz), 2.92 (1H, dd, J =16.54, 4.41 Hz), 3.18 (3H, s), 3.25 (1H, dd, J = 5.07, 4.41 Hz), 3.34(4H, s), 6.65 (1H, s), 6.88 (1H, d, J = 8.16 Hz), 7.24 (1H, s), 7.56(1H, d, J = 8.16 Hz), 11.38 (1H, s), 12.55 (1H, s). 381 379

TABLE 1-77 Ex. MS MS No. structural formula NMR (M + H) (M − H) 373

¹H-NMR (DMSO-D₆) δ: 0.91 (3H, t, J = 7.45 Hz), 0.96 (6H, s), 2.01 (2H,q, J = 7.45 Hz), 2.37 (1H, d, J = 16.12 Hz), 2.53-2.61 (1H, m), 2.57(1H, d, J = 16.12 Hz), 2.83-2.92 (1H, m), 3.18 (3H, s), 3.58-3.61 (1H,m), 4.70 (1H, d, J = 4.84 Hz), 6.55 (1H, s), 6.86 (1H, d, J = 8.46 Hz),7.23 (1H, s), 7.55 (1H, d, J = 8.46 Hz), 11.35 (1H, s), 12.50 (1H, s).367 365 374

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.57 (2H, t, J = 6.25 Hz), 2.04 (3H,s), 2.40 (2H, s), 2.60-2.68 (2H, m), 6.48 (1H, s), 7.04 (1H, dd, J =8.46, 1.61 Hz), 7.37 (1H, d, J = 8.46 Hz), 7.87 (1H, s), 9.78 (1H, s),11.12 (1H, s), 12.42 (1H, s). 323 321 375

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.21 (3H, d, J = 6.85 Hz), 1.57 (2H,t, J = 6.25 Hz), 2.40 (2H, s), 2.49-2.69 (6H, m), 3.22 (1H, q, J = 6.85Hz), 3.58- 3.67 (4H, m), 6.49 (1H, s), 7.08 (1H, d, J = 8.46 Hz), 7.39(1H, d, J = 8.46 Hz), 7.89 (1H, s), 9.65 (1H, s), 11.17 (1H, s), 12.44(1H, s). 422 420

TABLE 1-78 Ex. MS MS No. structural formula NMR (M + H) (M − H) 376

¹H-NMR (DMSO-D₆) δ: 0.98 (d, 3H, J = 6.45 Hz), 1.01 (s, 6H), 1.58 (t,2H, J = 6.25 Hz), 2.23-2.29 (m, 1H), 2.41 (s, 2H), 2.49-2.56 (m, 1H),2.66-2.69 (m, 2H), 3.17 (q, 1H, J = 6.72 Hz), 3.22 (s, 3H), 4.39-4.41(m, 1H), 6.62 (s, 1H), 6.87 (d, 1H, J = 8.26 Hz), 7.26 (s, 1H), 7.57 (d,1H, J = 8.26 Hz), 11.38 (s, 1H), 12.54 (s, 1H). 410 408 377

¹H-NMR (DMSO-D₆) δ: 0.97 (d, 3H, J = 6.69 Hz), 1.01 (s, 6H), 1.58 (t,2H, J = 6.29 Hz), 2.41 (s, 2H), 2.63-2.72 (m, 2H), 3.19 (s, 3H), 3.37(q, 1H, J = 6.69 Hz), 6.61 (s, 1H), 6.91 (d, 1H, J = 8.16 Hz), 7.28 (s,1H), 7.56 (d, 1H, J = 8.16 Hz), 11.42 (s, 1H), 12.55 (s, 1H). 366 364378

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.01 (3H, d, J = 5.64 Hz), 1.58 (2H,t, J = 6.25 Hz), 2.41 (2H, s), 2.56- 2.72 (3H, m), 3.18 (3H, s),3.20-3.48 (5H, m), 3.62- 3.73 (1H, m), 4.44-4.54 (1H, m), 6.28-6.35 (1H,m), 6.59 (1H, s), 6.88 (1H, d, J = 8.46 Hz), 7.27 (1H, s), 7.54 (1H, d,J = 8.46 Hz), 11.39 (1H, s), 12.53 (1H, s). 452 450 379

¹H-NMR (DMSO-D6) δ: 1.01 (6H, s), 1.04 (3H, d, J = 6.85 Hz), 1.58 (2H,t, J = 6.25 Hz), 2.41 (2H, s), 2.58 (1H, q, J = 6.18 Hz), 2.68 (2H, t, J= 5.84 Hz), 3.05- 3.52 (10H, m), 6.61 (1H, s), 6.90 (1H, d, J = 8.46Hz), 7.30 (1H, s), 7.55 (1H, d, J = 8.46 Hz), 11.37 (1H, s), 12.52 (1H,s). 468 466 380

¹H-NMR (DMSO-D₆) δ: 1.01 (6H, s), 1.26 (3H, d, J = 6.72 Hz), 1.58 (2H,t, J = 6.15 Hz), 2.43 (2H, s), 2.68 (2H, t, J = 6.26 Hz), 3.05 (2H, s),3.28 (3H, s), 3.73 (2H, t, J = 5.10 Hz), 3.87 (1H, d, J = 5.80 Hz), 4.06(2H, s), 6.67 (1H, d, J = 1.39 Hz), 7.01 (1H, dd, J = 8.35, 1.86 Hz),7.39 (1H, s), 7.62 (1H, d, J = 8.12 Hz), 8.93 (1H, s), 9.20 (1H, s),11.58 (1H, s). 468 466 381

¹H-NMR (DMSO-D₆) δ: 1.00 (6H, s), 1.36 (3H, d, J = 5.8 Hz), 1.56-1.60(2H, m), 2.42 (2H, s), 2.66-2.69 (2H, m), 2.96-3.20 (2H, m), 3.23- 3.46(6H, m), 3.69-3.87 (4H, m), 6.60-6.66 (1H, m), 6.87-7.01 (1H, m), 7.27-7.37 (1H, m), 7.51-7.64 (1H, m), 10.44 (1H, br s), 11.54 (1H, br s),12.60 (1H, br s). 436 434

Experimental Example: ITK Inhibitory Activity (1) Preparation of hITKEnzyme

hITK enzyme was prepared by strongly expressing FLAG-tagged full-lengthhITK in Sf9 cells, and purifying same by anti-FLAG antibody column.

(2) Preparation of Biotinylated GST-SLP76

Biotinylated GST-SLP76 was prepared by strongly expressing GST-taggedSLP76 (aa95-175) in Escherichia coli, purifying same by glutathionsepharose column and biotinylating same.

(3) Preparation of Solution

(i) buffer for dilution: 20 mmol/L 3-(N-morpholino)propanesulfonic acid(pH 7.0) (DOJINDO LABORATORIES), 10 mmol/L magnesium chloride(Sigma-Aldrich Corporation), 1 mmol/L dithiothreitol (Nacalai Tesque,Inc.), 0.1% gelatin (Sigma-Aldrich Corporation)(ii) substrate solution: 0.2 μg/mL biotinylated GST-SLP76, 100 μmol/LATP (Sigma-Aldrich Corporation), prepared with buffer for dilution(iii) test compound solution: test compound, 50% dimethyl sulfoxide(DMSO), prepared with buffer for dilution(iv) enzyme solution: 50 ng/mL hITK enzyme, prepared with buffer fordilution(v) control solution: solution after removal of test compound from themixture of the above-mentioned (i), (ii) and (iii)(vi) blank solution: solution after removal of ATP from the mixture ofthe above-mentioned (i), (ii) and (iii)(vii) detection buffer: 0.1 μg/mL Anti-Phosphotyrosine (PT66)-Cryptate(Cisbio), 2.5 μg/mL streptavidin-binding XL665 (Cisbio), 50 mmol/L4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (pH 7.4) (NacalaiTesque, Inc.), mmol/L EDTA (NipponGene), 0.1% TritonX (Sigma-AldrichCorporation), 200 mmol/L potassium fluoride (Wako Pure ChemicalIndustries, Ltd.), 0.05% bovine serum albumin (Sigma-AldrichCorporation)

(4) Measurement of ITK Inhibitory Activity

A substrate solution (25 μL/well), a test compound solution (5 μL/well)and an enzyme solution (20 μL/well) were added into 96 well half-areawhite plate (plate, Corning Incorporated 3642) to start a kinasereaction. The plate was stood still at room temperature for 10 min.Then, a detection buffer (50 μL/well) was added to the plate. After 2 hrfrom the addition of the detection buffer, fluorescence intensity at 620nm (excited at 337 nm), and fluorescence intensity at 665 nm (excited at620 nm) were measured by a fluorescence microplate reader.

The Ratio (fluorescence intensity at 665 nm/fluorescence intensity at620 nm×10000) of each test compound was calculated from the measuredfluorescence intensity. Simultaneously, the measurement was performedusing a blank solution and a control solution, and % of control value ofeach test compound was calculated from the following formula.

% of control=(Ratio of test compound−Ratio of blank)/(Ratio ofcontrol−Ratio of blank)×100 ITK inhibitory rate (%)=100−(% of control)

The IC₅₀ value was calculated from the test compound concentrations at 2points sandwiching 50% ITK inhibitory rate. The results are shown inTable 2 in nM values. The numerical value in % in the Table shows theITK inhibitory rate (%) at the concentration indicated in theparenthesis.

TABLE 2-1 Ex. No. ITK IC₅₀ (nM) 1 7 2 5 3 39 4 2 5 3 6 2 7 39 8 3 9 33410 45 11 36 12 33 13 99 14 40 15 9 16 25 17 5 18 45 19 23 20 47 21 30 2240 23 18 24 25 25 26 26 85 27 327 28 201 29 85 30 10 31 34 32 4 33 11 345 35 5 36 <3 37 8 38 5 39 4 40 6 41 4 42 22 43 6 44 <3 45 <3 46 5 47 848 6 49 3 50 4 51 26 52 <3 53 8 54 18

TABLE 2-2 Ex. No. ITK IC₅₀ (nM) 55 <3 56 <3 57 17 58 6 59 7 60 5 61 6 624 63 6 64 6 65 55 66 3 67 4 68 7 69 4 70 3 71 <3 72 9 73 <3 74 4 75 3476 4 77 6 78 7 79 13 80 3 81 8 82 7 83 <3 84 <3 85 4 86 <3 87 <3 88 3 89<3 90 4 91 13 92 10 93 48 94 4 95 3 96 3 97 20 98 3 99 26 100 5 101 13102 117 103 3 104 4 105 2 106 7 107 10 108 15

TABLE 2-3 Ex. No. ITK IC₅₀ (nM) 109 6 110 7 111 9 112 7 113 9 114 5 1154 116 9 117 6 118 3 119 3 120 5 121 5 122 20 123 2 124 12 125 1 126 8127 1 128 2 129 5 130 2 131 25 132 13 133 10 134 8 135 6 136 2 137 2 1383 139 2 140 2 141 10 142 5 143 3 144 9 145 3 146 11 147 8 148 19 149 10150 2 151 3 152 14 153 5 154 2 155 9 156 <1 157 1 158 5 159 7 160 1 16122 162 1

TABLE 2-4 Ex. No. ITK IC₅₀ (nM) 163 1 164 3 165 5 166 1 167 1 168 3 1693 170 <1 171 1 172 2 173 13 174 2 175 2 176 7 177 2 178 4 179 1 180 <1181 1 182 2 183 1 184 1 185 2 186 1 187 2 188 1 189 1 190 4 191 7 192 2193 2 194 2 195 20 196 4 197 2 198 1 199 2 200 1 201 10 202 14 203 12204 49.2% (30 nM) 205 27 206 5 207 4 208 29 209 4 210 36 211 33 212 5213 <3 214 <3 215 <3 216 8

TABLE 2-5 Ex. No. ITK IC₅₀ (nM) 217 <3 218 <3 219 4 220 <3 221 3 222 <3223 5 224 1 225 2 226 2 227 34 228 40 229 38 230 25 231 2 232 3 233 10234 16 235 8 236 6 237 2 238 2 239 5 240 3 241 23 242 3 243 24 244 23245 10 246 7 247 4 248 2 249 7 250 139 251 34 252 11 253 2 254 5 255 3256 1 257 1 258 4 259 3 260 <1 261 1 262 3 263 7 264 10 265 2 266 7 2675 268 5 269 6 270 2

TABLE 2-6 Ex. No. ITK IC₅₀ (nM) 271 3 272 3 273 11 274 9 275 2 276 4 2771 278 1 279 <1 280 2 281 1 282 2 283 2 284 1 285 2 286 2 287 1 288 1 289<1 290 8 291 1 292 2 293 263 294 51 295 138 296 58 297 48 298 44 299 74300 221 301 37 302 39 303 33 304 27 305 13 306 27 307 61 308 49 309 102310 47 311 32 312 27 313 47 314 143 315 60 316 47 317 21 318 45 319 46320 49 321 48 322 41 323 34 324 140

TABLE 2-7 Ex. No. ITK IC₅₀ (nM) 325 246 326 42 327 132 328 26 329 13 33080 331 60 332 46 333 106 334 31 335 26 336 78 337 49 338 33 339 842 340129 341 333 342 245 343 135 344 278 345 88 346 5 347 4 348 8 349 2 35062 351 24 352 37 353 16 354 16 355 9 356 9 357 29 358 38 359 21 360 67361 20 362 12 363 485 364 45 365 45 366 82 367 75 368 131 369 207 370204 371 112 372 11 373 8 374 130 375 110

TABLE 2-8 Ex. No. ITK IC₅₀ (nM) 376 2 377 6 378 2 379 4 380 2 381 2

In the test for the compounds of Examples 380 and 381, the ATPconcentration of the substrate solutions was 6 μmol/L.

From the above results, it is clear that the compound of the presentinvention has an ITK inhibitory action.

Formulation Example 1 (Production of Capsule)

1) compound of Example 1 30 mg 2) microcrystalline cellulose 10 mg 3)lactose 19 mg 4) magnesium stearate  1 mg

1), 2), 3) and 4) are mixed and filled in a gelatin capsule.

Formulation Example 2 (Production of Tablet)

1) compound of Example 1 10 g 2) lactose 50 g 3) cornstarch 15 g 4)carmellose calcium 44 g 5) magnesium stearate  1 g

The entire amounts of 1), 2) and 3) and 30 g of 4) are kneaded withwater, vacuum dried and sieved. The sieved powder is mixed with 14 g of4) and 1 g of 5), and the mixture is tableted by a tableting machine. Inthis way, 1000 tablets each containing 10 mg of the compound of Example1 per tablet are obtained.

INDUSTRIAL APPLICABILITY

Hence, the indole compound of the present invention can be a medicamenteffective for the treatment or prophylaxis of inflammatory diseases,allergic diseases, autoimmune diseases, transplant rejection and thelike.

1.-26. (canceled)
 27. A process for producing a compound of formula [I]

or a pharmaceutically acceptable salt thereof comprising contacting acompound of formula [1]

with a compound of formula [2]

to form a compound of formula [3]

 and converting the compound of formula [3] to the compound of formula[I], wherein R¹ is (1) a hydrogen atom, (2) a hydroxy group, or (3) aC₁₋₆ alkoxy group optionally substituted by C₆₋₁₀ aryl group(s); R² andR³ are the same or different and each is (1) a hydrogen atom, or (2) aC₁₋₆ alkyl group optionally substituted by 1 to 3 substituents selectedfrom (a) a hydroxy group, and (b) a C₁₋₆ alkoxy group; R⁴ is a groupselected from

 which is bonded to the 5-position or the 6-position of the indole ring,wherein R⁵ is (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group, and R⁶ is(1) a hydrogen atom, (2) a C₁₋₆ alkyl group optionally substituted by 1to 3 substituents selected from (a) a hydroxy group, (b) a C₁₋₆ alkoxygroup, (c) a carboxy group, (d) a C₁₋₆ alkoxy-carbonyl group, (e) aC₆₋₁₀ aryl group, (f) a C₆₋₁₀ aryloxy group, (g) an amino groupoptionally mono- or di-substituted by C₁₋₆ alkyl group(s), (h) a 5- or6-membered unsaturated heterocyclic group optionally substituted by C₁₋₆alkyl group(s), and (i) a 5- or 6-membered saturated heterocyclic group,(3) a C₁₋₆ alkoxy group, (4) a C₆₋₁₀ aryl group, or (5) a 5- or6-membered unsaturated heterocyclic group optionally substituted by 1 to3 substituents selected from (a) a hydroxy group, and (b) a C₁₋₆ alkoxygroup, or R⁵ and R⁶ form, together with the nitrogen atom they arebonded to, a 5- or 6-membered cyclic amine, wherein said cyclic amine isoptionally condensed with a 5- or 6-membered unsaturated heterocycle,that is optionally substituted by 1 to 3 substituents selected from (a)a hydroxy group, (b) a C₁₋₆ alkyl group, (c) a C₁₋₆ alkoxy group, and(d) a C₁₋₆ alkoxy-carbonyl group; R⁷ is (1) a hydrogen atom, or (2) aC₁₋₆ alkyl group optionally substituted by 1 to 3 substituents selectedfrom (a) a hydroxy group, (b) a C₁₋₆ alkoxy group, and (c) an aminogroup optionally mono- or di-substituted by C₁₋₆ alkyl group(s), R⁸ is(1) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from (a) a hydroxy group, (b) a C₁₋₆ alkoxy group optionallysubstituted by C₆₋₁₀aryl group(s), (c) a C₃₋₆ cycloalkyl groupoptionally substituted by C₁₋₆ alkoxy group(s), (d) a C₆₋₁₀ aryl group,(e) a 5- or 6-membered unsaturated heterocyclic group optionallysubstituted by oxo group(s), (f) a 5- to 8-membered saturatedheterocyclic group optionally substituted by 1 to 3 substituentsselected from  (i) a hydroxy group,  (ii) a C₁₋₆ alkyl group optionallysubstituted by 1 to 3 substituents selected from a hydroxy group and aC₁₋₆ alkoxy group,  (iii) a C₁₋₆ alkoxy group, and  (iv) an oxo group,(g) a C₃₋₆ cycloalkyloxy group, (h) a C₆₋₁₀ aryloxy group, (i) a 5- or6-membered unsaturated heterocyclyloxy group, (j) a 5- or 6-memberedsaturated heterocyclyloxy group, and (k) an amino group optionally mono-or di-substituted by substituents selected from  (i) a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 substituents selected from a hydroxygroup, a carboxy group and a carboxy-C₁₋₆ alkoxy group,  (ii) a C₁₋₆alkyl-carbonyl group optionally substituted by 1 to 3 substituentsselected from a hydroxy group and a C₁₋₆ alkoxy group,  (iii) a C₁₋₆alkoxy-carbonyl group optionally substituted by C₆₋₁₀ aryl group(s), and (iv) a C₃₋₆ cycloalkyl-carbonyl group optionally substituted by C₁₋₆alkoxy group(s), (2) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀aryl group(s), (3) a C₃₋₆ cycloalkyl group optionally substituted by 1to 3 substituents selected from (a) a hydroxy group, and (b) a C₁₋₆alkoxy group, (4) a C₆₋₁₀ aryl group optionally substituted by C₁₋₆alkyl group(s) optionally substituted by 1 to 3 halogen atoms, (5) anamino group optionally mono- or di-substituted by C₁₋₆ alkyl group(s)optionally substituted by C₆₋₁₀ aryl group(s), (6) a 5- or 6-memberedunsaturated heterocyclic group optionally substituted by C₁₋₆ alkylgroup(s), (7) a 5- or 6-membered saturated heterocyclic group optionallysubstituted by 1 to 3 substituents selected from (a) a C₁₋₆ alkyl group,(b) a C₁₋₆ alkyl-carbonyl group, and (c) an oxo group, (8) a C₃₋₆cycloalkyloxy group, or (9) a C₆₋₁₀aryl-carbonyl group, or R⁷ and R⁸form, together with the nitrogen atom and carbon atom they are bondedto, a 5- or 6-membered cyclic amine substituted by an oxo group andoptionally further substituted by 1 to 3 substituents selected from (a)a hydroxy group, (b) a C₁₋₆ alkyl group optionally substituted byhydroxy group(s), (c) a C₁₋₆ alkoxy group, and (d) a C₃₋₆ cycloalkylgroup; and R⁹ and R¹⁰ are the same or different and each is anamino-protecting group selected from the group consisting of atert-butoxycarbonyl group, an ethoxycarbonyl group, a trityl group, atetrahydropyranyl group, a methoxymethyl group, a2-(trimethylsilyl)ethoxymethyl group, and a p-toluenesulfonyl group. 28.A compound of formula [1]

wherein R¹ is (1) a hydrogen atom, (2) a hydroxy group, or (3) a C₁₋₆alkoxy group optionally substituted by C₆₋₁₀aryl group(s); R² and R³ arethe same or different and each is a C₁₋₆ alkyl group optionallysubstituted by 1 to 3 substituents selected from (a) a hydroxy group,and (b) a C₁₋₆ alkoxy group; and R⁹ is an amino-protecting groupselected from the group consisting of a tert-butoxycarbonyl group, anethoxycarbonyl group, a trityl group, a tetrahydropyranyl group, amethoxymethyl group, a 2-(trimethylsilyl)ethoxymethyl group, and ap-toluenesulfonyl group.
 29. A compound of formula [2]

wherein R⁴ is a group selected from

 which is bonded to the 5-position or the 6-position of the indole ring,wherein R⁵ is (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group, and R⁶ is(1) a hydrogen atom, (2) a C₁₋₆ alkyl group optionally substituted by 1to 3 substituents selected from (a) a hydroxy group, (b) a C₁₋₆ alkoxygroup, (c) a carboxy group, (d) a C₁₋₆ alkoxy-carbonyl group, (e) aC₆₋₁₀ aryl group, (f) a C₆₋₁₀ aryloxy group, (g) an amino groupoptionally mono- or di-substituted by C₁₋₆ alkyl group(s), (h) a 5- or6-membered unsaturated heterocyclic group optionally substituted by C₁₋₆alkyl group(s), and (i) a 5- or 6-membered saturated heterocyclic group,(3) a C₁₋₆ alkoxy group, (4) a C₆₋₁₀ aryl group, or (5) a 5- or6-membered unsaturated heterocyclic group optionally substituted by 1 to3 substituents selected from (a) a hydroxy group, and (b) a C₁₋₆ alkoxygroup, or R⁵ and R⁶ form, together with the nitrogen atom they arebonded to, a 5- or 6-membered cyclic amine, wherein said cyclic amine isoptionally condensed with a 5- or 6-membered unsaturated heterocycle,that is optionally substituted by 1 to 3 substituents selected from (a)a hydroxy group, (b) a C₁₋₆ alkyl group, (c) a C₁₋₆ alkoxy group, and(d) a C₁₋₆ alkoxy-carbonyl group; R⁷ is a C₁₋₆ alkyl group optionallysubstituted by 1 to 3 substituents selected from (a) a hydroxy group,(b) a C₁₋₆ alkoxy group, and (c) an amino group optionally mono- ordi-substituted by C₁₋₆ alkyl group(s), R⁸ is (1) a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 substituents selected from (a) ahydroxy group, (b) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀aryl group(s), (c) a C₃₋₆ cycloalkyl group optionally substituted byC₁₋₆ alkoxy group(s), (d) a C₆₋₁₀ aryl group, (e) a 5- or 6-memberedunsaturated heterocyclic group optionally substituted by oxo group(s),(f) a 5- to 8-membered saturated heterocyclic group optionallysubstituted by 1 to 3 substituents selected from  (i) a hydroxy group, (ii) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from a hydroxy group and a C₁₋₆ alkoxy group,  (iii) a C₁₋₆alkoxy group, and  (iv) an oxo group, (g) a C₃₋₆ cycloalkyloxy group,(h) a C₆₋₁₀ aryloxy group, (i) a 5- or 6-membered unsaturatedheterocyclyloxy group, (j) a 5- or 6-membered saturated heterocyclyloxygroup, and (k) an amino group optionally mono- or di-substituted bysubstituents selected from  (i) a C₁₋₆ alkyl group optionallysubstituted by 1 to 3 substituents selected from a hydroxy group, acarboxy group and a carboxy-C₁₋₆ alkoxy group,  (ii) a C₁₋₆alkyl-carbonyl group optionally substituted by 1 to 3 substituentsselected from a hydroxy group and a C₁₋₆ alkoxy group,  (iii) a C₁₋₆alkoxy-carbonyl group optionally substituted by C₆₋₁₀ aryl group(s), and (iv) a C₃₋₆ cycloalkyl-carbonyl group optionally substituted by C₁₋₆alkoxy group(s), (2) a C₁₋₆ alkoxy group optionally substituted byC₆₋₁₀aryl group(s), (3) a C₃₋₆ cycloalkyl group optionally substitutedby 1 to 3 substituents selected from (a) a hydroxy group, and (b) a C₁₋₆alkoxy group, (4) a C₆₋₁₀ aryl group optionally substituted by C₁₋₆alkyl group(s) optionally substituted by 1 to 3 halogen atoms, (5) anamino group optionally mono- or di-substituted by C₁₋₆ alkyl group(s)optionally substituted by C₆₋₁₀aryl group(s), (6) a 5- or 6-memberedunsaturated heterocyclic group optionally substituted by C₁₋₆ alkylgroup(s), (7) a 5- or 6-membered saturated heterocyclic group optionallysubstituted by 1 to 3 substituents selected from (a) a C₁₋₆ alkyl group,(b) a C₁₋₆ alkyl-carbonyl group, and (c) an oxo group, (8) a C₃₋₆cycloalkyloxy group, or (9) a C₆₋₁₀ aryl-carbonyl group, or R⁷ and R⁸form, together with the nitrogen atom and carbon atom they are bondedto, a 5- or 6-membered cyclic amine substituted by an oxo group andoptionally further substituted by 1 to 3 substituents selected from (a)a hydroxy group, (b) a C₁₋₆ alkyl group optionally substituted byhydroxy group(s), (c) a C₁₋₆ alkoxy group, and (d) a C₃₋₆ cycloalkylgroup; and R¹⁰ is an amino-protecting group selected from the groupconsisting of a tert-butoxycarbonyl group, an ethoxycarbonyl group, atrityl group, a tetrahydropyranyl group, a methoxymethyl group, a2-(trimethylsilyl)ethoxymethyl group, and a p-toluenesulfonyl group. 30.A compound of formula [3]

wherein R¹ is (1) a hydrogen atom, (2) a hydroxy group, or (3) a C₁₋₆alkoxy group optionally substituted by C₆₋₁₀ aryl group(s); R² and R³are the same or different and each is a C₁₋₆ alkyl group optionallysubstituted by 1 to 3 substituents selected from (a) a hydroxy group,and (b) a C₁₋₆ alkoxy group; R⁴ is a group selected from

 which is bonded to the 5-position or the 6-position of the indole ring,wherein R⁵ is (1) a hydrogen atom, or (2) a C₁₋₆ alkyl group, and R⁶ is(1) a hydrogen atom, (2) a C₁₋₆ alkyl group optionally substituted by 1to 3 substituents selected from (a) a hydroxy group, (b) a C₁₋₆ alkoxygroup, (c) a carboxy group, (d) a C₁₋₆ alkoxy-carbonyl group, (e) aC₆₋₁₀ aryl group, (f) a C₆₋₁₀ aryloxy group, (g) an amino groupoptionally mono- or di-substituted by C₁₋₆ alkyl group(s), (h) a 5- or6-membered unsaturated heterocyclic group optionally substituted by C₁₋₆alkyl group(s), and (i) a 5- or 6-membered saturated heterocyclic group,(3) a C₁₋₆ alkoxy group, (4) a C₆₋₁₀ aryl group, or (5) a 5- or6-membered unsaturated heterocyclic group optionally substituted by 1 to3 substituents selected from (a) a hydroxy group, and (b) a C₁₋₆ alkoxygroup, or R⁵ and R⁶ form, together with the nitrogen atom they arebonded to, a 5- or 6-membered cyclic amine, wherein said cyclic amine isoptionally condensed with a 5- or 6-membered unsaturated heterocycle,that is optionally substituted by 1 to 3 substituents selected from (a)a hydroxy group, (b) a C₁₋₆ alkyl group, (c) a C₁₋₆ alkoxy group, and(d) a C₁₋₆ alkoxy-carbonyl group; R⁷ is a C₁₋₆ alkyl group optionallysubstituted by 1 to 3 substituents selected from (a) a hydroxy group,(b) a C₁₋₆ alkoxy group, and (c) an amino group optionally mono- ordi-substituted by C₁₋₆ alkyl group(s), R⁸ is (1) a C₁₋₆ alkyl groupoptionally substituted by 1 to 3 substituents selected from (a) ahydroxy group, (b) a C₁₋₆ alkoxy group optionally substituted byC₆₋₁₀aryl group(s), (c) a C₃₋₆ cycloalkyl group optionally substitutedby C₁₋₆ alkoxy group(s), (d) a C₆₋₁₀ aryl group, (e) a 5- or 6-memberedunsaturated heterocyclic group optionally substituted by oxo group(s),(f) a 5- to 8-membered saturated heterocyclic group optionallysubstituted by 1 to 3 substituents selected from  (i) a hydroxy group, (ii) a C₁₋₆ alkyl group optionally substituted by 1 to 3 substituentsselected from a hydroxy group and a C₁₋₆ alkoxy group,  (iii) a C₁₋₆alkoxy group, and  (iv) an oxo group, (g) a C₃₋₆ cycloalkyloxy group,(h) a C₆₋₁₀ aryloxy group, (i) a 5- or 6-membered unsaturatedheterocyclyloxy group, (j) a 5- or 6-membered saturated heterocyclyloxygroup, and (k) an amino group optionally mono- or di-substituted bysubstituents selected from  (i) a C₁₋₆ alkyl group optionallysubstituted by 1 to 3 substituents selected from a hydroxy group, acarboxy group and a carboxy-C₁₋₆ alkoxy group,  (ii) a C₁₋₆alkyl-carbonyl group optionally substituted by 1 to 3 substituentsselected from a hydroxy group and a C₁₋₆ alkoxy group,  (iii) a C₁₋₆alkoxy-carbonyl group optionally substituted by C₆₋₁₀ aryl group(s), and (iv) a C₃₋₆ cycloalkyl-carbonyl group optionally substituted by C₁₋₆alkoxy group(s), (2) a C₁₋₆ alkoxy group optionally substituted by C₆₋₁₀aryl group(s), (3) a C₃₋₆ cycloalkyl group optionally substituted by 1to 3 substituents selected from (a) a hydroxy group, and (b) a C₁₋₆alkoxy group, (4) a C₆₋₁₀ aryl group optionally substituted by C₁₋₆alkyl group(s) optionally substituted by 1 to 3 halogen atoms, (5) anamino group optionally mono- or di-substituted by C₁₋₆ alkyl group(s)optionally substituted by C₆₋₁₀ aryl group(s), (6) a 5- or 6-memberedunsaturated heterocyclic group optionally substituted by C₁₋₆ alkylgroup(s), (7) a 5- or 6-membered saturated heterocyclic group optionallysubstituted by 1 to 3 substituents selected from (a) a C₁₋₆ alkyl group,(b) a C₁₋₆ alkyl-carbonyl group, and (c) an oxo group, (8) a C₃₋₆cycloalkyloxy group, or (9) a C₆₋₁₀ aryl-carbonyl group, or R⁷ and R⁸form, together with the nitrogen atom and carbon atom they are bondedto, a 5- or 6-membered cyclic amine substituted by an oxo group andoptionally further substituted by 1 to 3 substituents selected from (a)a hydroxy group, (b) a C₁₋₆ alkyl group optionally substituted byhydroxy group(s), (c) a C₁₋₆ alkoxy group, and (d) a C₃₋₆ cycloalkylgroup; and R⁹ and R¹⁰ are the same or different and each is anamino-protecting group selected from the group consisting of atert-butoxycarbonyl group, an ethoxycarbonyl group, a trityl group, atetrahydropyranyl group, a methoxymethyl group, a2-(trimethylsilyl)ethoxymethyl group, and a p-toluenesulfonyl group.